Heterocyclic modulators of lipid synthesis

ABSTRACT

Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.14/587,908, which was filed on Dec. 31, 2014 (now allowed), which is acontinuation of International PCT Patent Application No.PCT/US2013/048950, which was filed on Jul. 1, 2013, which claims thebenefit under 35 U.S.C. §119(e) of U.S. Provisional Patent ApplicationNo. 61/667,894, filed Jul. 3, 2012, U.S. Provisional Patent ApplicationNo. 61/698,511, filed Sep. 7, 2012, U.S. Provisional Patent ApplicationNo. 61/699,819, filed Sep. 11, 2012, and U.S. Provisional PatentApplication No. 61/785,933, filed Mar. 14, 2103. The foregoingapplications are incorporated herein by reference in their entireties.

FIELD

The present disclosure relates generally to heterocyclic modulators oflipid synthesis and methods of use thereof. The present heterocyclicmodulators of lipid synthesis can be used for the treatment of disorderscharacterized by disregulation in the fatty acid synthase function in asubject by modulating the fatty acid synthase pathway and/or the fattyacid synthase function.

BACKGROUND

Viral disease is a significant health concern that threatens largesegments of human populations. Some of the features related to viralinfection which are of concern to health care professionals include itshighly contagious nature (e.g., HIV, SARS, etc.) and high mutability.Some viruses are also oncogenic (such as HPV, EBV and HBV). Whileviruses are structurally amongst the simplest of organisms, they areregarded to be among the most difficult to control and present aformidable challenge for antiviral drug R&D.

Thus far, there have been a few antiviral drugs widely used in patients,such as Amantadine and Oseltamivir for influenza, Acyclovir forHSV-related infections, Ganciclovir for CMV infection, and multipleagents including co-formulated drugs (Efavirenz, emtricitabine, andtonfovir disoproxil fumarate) for AIDS treatments. These drugs possess avariety of undesirable neurological, metabolic and immunologicalside-effects. Therefore, development of new antiviral therapy has becomea major focus of medical and pharmaceutical research and development.

Infection by hepatitis C virus (HCV) is a serious health issue. It isestimated that 170 million people worldwide are chronically infectedwith HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liverfailure and hepatocellular carcinoma. Chronic HCV infection is thus amajor worldwide cause of liver-related premature mortality.

The present standard of care treatment regimen for HCV infectioninvolves combination therapy with interferon-alpha and ribavirin, oftenwith the addition of a direct-acting protease inhibitor (Telaprevir orBoceprevir). The treatment is cumbersome and sometimes has debilitatingand severe side effects. For this reason, many patients are not treatedin early stages of the disease. Additionally, some patient populationsdo not durably respond to treatment. New and effective methods oftreating HCV infection are urgently needed.

The dominant therapeutic approaches that are currently employed to treatcancer include surgical removal of primary tumors, tumor irradiation,and parenteral application of anti-mitotic cytotoxic agents.Unfortunately, only a relatively small cross-section of cancer patientshave tumors that are “addicted” to a specific pathway, and can thereforebe treated with newer targeted agents. The continued dominance of theselong established therapies is mirrored by the lack of improvement insurvival rates for most cancers. In addition to limited clinicalsuccess, devastating side effects accompany classic therapies. Bothradiation- and cytotoxic-based therapies result in the destruction ofrapidly dividing hematopoietic and intestinal epithelial cells leadingto compromised immune function, anemia, and impaired nutrientabsorption. Surgical intervention often results in a release of tumorcells into the circulation or lymph systems from which metastatic tumorscan subsequently be established. Improved methods for the treatment ofcancer are needed.

SUMMARY

The present disclosure addresses the deficiencies for antiviral andanticancer treatments by providing novel heterocyclic modulators oflipid synthesis having improved antiviral and anticancer activities.

In various aspects, the present disclosure provides for compounds ofStructure I:

or pharmaceutically acceptable salts thereof, wherein:

-   L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—,    wherein R⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered    heterocycle;-   n is 1, 2, or 3;-   m is 1 or 2 with the proviso that n+m≧3;-   L-Ar is

-   Ar is

with the proviso that when L-Ar is

Ar is not

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to    6-membered heterocycle; and-   R²² is H, halogen, or C₁-C₂ alkyl.

In various aspects, the present disclosure provides for compounds ofStructure II:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

with the proviso that when L-Ar is

Ar is not

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen, or C₁-C₂ alkyl; and-   R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄    alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl),    —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄    alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:    -   each t is independently 0 or 1; and    -   each R²⁴¹ is independently H or C₁-C₂ alkyl.

In various aspects, the present disclosure provides for compounds ofStructure III:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen, or C₁-C₂ alkyl;-   R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,    —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆    cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle)    or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein:    -   t is 0 or 1;    -   u is 0 or 1;    -   with the proviso that when u is 1, t is 1; and    -   each R²⁴¹ is independently H or C₁-C₂ alkyl; and-   R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl.

In various aspects, the present disclosure provides for compounds ofStructure IIIb:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen or C₁-C₂ alkyl; and-   each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄    alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,    —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃—C cycloalkyl), —(C₁-C₄    alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄    alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:    -   each t is independently 0 or 1;    -   each u is independently 0 or 1; and    -   each R²⁴¹ is independently H or C₁-C₂ alkyl,        wherein the compound is not:

In various aspects, the present disclosure provides for compounds ofStructure IIIc:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen or C₁-C₂ alkyl; and-   each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen.

In various aspects, the present disclosure provides for compounds ofStructure IV:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

with the proviso that when L-Ar is

Ar is not

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen or C₁-C₂ alkyl; and-   R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,    —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄    alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄    alkyl)-O—(C₁-C₄ alkyl), wherein:    -   t is 0 or 1;    -   u is 0 or 1;    -   with the proviso that when u is 1, t is 1; and    -   R²⁴¹ is H or C₁-C₂ alkyl.

In various aspects, the present disclosure provides for compounds ofStructure V:

or pharmaceutically acceptable salts thereof, wherein:

-   -   L-Ar is

-   -   Ar is

with the proviso that when L-Ar is

Ar is not

-   -   L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅        cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;    -   Het is a 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl),        —O-(4- to 6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when        R¹ is not H, —CN or halogen, R¹ is optionally substituted with        one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to        6-membered heterocycle;    -   R²² is H, halogen, or C₁-C₂ alkyl; and    -   R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein        R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered        heterocycle, aryl or heteroaryl.

In various aspects the present disclosure provides for compounds ofStructure VI:

or pharmaceutically acceptable salts thereof, wherein:

-   -   each W, X, Y and Z is independently —N— or —CR²⁶— with the        proviso that not more than 2 of W, X, Y and Z are —N—;    -   each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl),        —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);    -   each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄        alkyl and join to form a 3- to 6-membered ring together with the        N to which they are attached and wherein the ring optionally        includes one oxygen atom as one of the members of the ring;    -   Ar is

-   -   Het is a 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl),        —O-(4- to 6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when        R¹ is not H, —CN or halogen, R¹ is optionally substituted with        one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to        6-membered heterocycle; and    -   R²² is H, halogen or C₁-C₂ alkyl.

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Structures I, II,III, IIIb, IIIc, IV, V and VI and a pharmaceutically acceptable carrier,excipient, or diluent.

In various aspects, the present disclosure provides methods of treatinga condition characterized by disregulation of a fatty acid synthasepathway in subject, the method comprising administering to a subject inneed of such treatment an effective amount of a compound of any one ofthe Structures I, II, III, IIIb, IIIc, IV, V and VI. In various aspects,the condition characterized by disregulation of a fatty acid synthasepathway is a viral infection or cancer. In various aspects, the viralinfection is treated using a compound of any one of the Structures I,II, III, IIIb, IIIc, IV, V and VI in combination with one or moreadditional antiviral treatments. In various aspects, the cancer istreated using a compound of any one of the Structures I, II, III, IIIb,IIIc, IV, V and VI in combination with one or more additional cancertreatments. In various aspects, the viral infection is hepatitis C. Invarious aspects, the cancer is breast cancer. In various aspects, thecancer is pancreatic cancer. In various aspects, the cancer is coloncancer.

DETAILED DESCRIPTION

The present disclosure addresses the deficiencies in treating conditionscharacterized by disregulation of the FASN function in a subject, suchas viral infection, cancer and metabolic disorders, by providing novelheterocyclic modulators of lipid synthesis.

In certain aspects, the present disclosure provides compositions andmethods for treatment of viral infections. In general, the compositionsand methods for treatment of viral infections are directed towardmodulation of the fatty acid synthesis pathway. The fatty acid synthesispathway is involved in the replication of viruses in the host cells. Thepresent invention embodies methods for the treatment of viral infectionsthat interact with the fatty acid synthesis pathway, such as hepatitisC.

In certain aspects, the present disclosure provides compositions andmethods for the treatment of cancer. Fatty acid synthase is responsiblefor conversion of malonyl-CoA into long-chain fatty acids, which is anearly reaction in fatty acid biosynthesis. Fatty acid synthase isoverexpressed in many cancer cells. Without being bound by anyparticular theory, it is hypothesized that inhibition of fatty acidsynthase expression or fatty acid synthase activity selectivitysuppresses proliferation and induces cell death of cancer cells, withlittle toxicity towards normal cells.

Further, the present disclosure provides compounds and methods formodulating host cell targets that are targeted by viruses. Suchmodulation of host cell targets can include either activation orinhibition of the host cell targets. Accordingly, compounds thatmodulate components of the fatty acid synthesis pathway, such as theactivity of a non-viral protein, e.g., a host cell protein, can be usedas antiviral pharmaceutical agents.

DEFINITIONS

Chemical moieties referred to as univalent chemical moieties (e.g.,alkyl, aryl, etc.) also encompass structurally permissible multivalentmoieties, as understood by those skilled in the art. For example, whilean “alkyl” moiety generally refers to a monovalent radical (e.g.,CH₃CH₂—), in appropriate circumstances an “alkyl” moiety can also referto a divalent radical (e.g., —CH₂CH₂—, which is equivalent to an“alkylene” group). Similarly, under circumstances where a divalentmoiety is required, those skilled in the art will understand that theterm “aryl” refers to the corresponding divalent arylene group.

All atoms are understood to have their normal number of valences forbond formation (e.g., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the atom's oxidation state). On occasion a moiety can bedefined, for example, as (A)_(a)B, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B and when a is 1 the moiety is AB.

Where a substituent can vary in the number of atoms or groups of thesame kind (e.g., alkyl groups can be C₁, C₂, C₃, etc.), the number ofrepeated atoms or groups can be represented by a range (e.g., C₁-C₆alkyl) which includes each and every number in the range and any and allsub ranges. For example, C₁-C₃ alkyl includes C₁, C₂, C₃, C₁₋₂, C₁₋₃,and C₂₋₃ alkyl.

“Alkanoyl” refers to a carbonyl group with a lower alkyl group as asubstituent.

“Alkylamino” refers to an amino group substituted by an alkyl group.

“Alkoxy” refers to an O-atom substituted by an alkyl group as definedherein, for example, methoxy [—OCH₃, a C₁alkoxy]. The term “C₁₋₆ alkoxy”encompasses C₁ alkoxy, C₂ alkoxy, C₃ alkoxy, C₄ alkoxy, C₅ alkoxy, C₆alkoxy, and any sub-range thereof.

“Alkoxycarbonyl” refers to a carbonyl group with an alkoxy group as asubstituent.

“Alkylcarbonyloxy” refers to the group —O—(C═O)-alkyl.

“Alkyl,” “alkenyl,” and “alkynyl,” refer to optionally substituted,straight and branched chain aliphatic groups having from 1 to 30 carbonatoms, or preferably from 1 to 15 carbon atoms, or more preferably from1 to 6 carbon atoms. Examples of alkyl groups include, withoutlimitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, andpropynyl. The term “heteroalkyl” as used herein contemplates an alkylwith one or more heteroatoms. The term “haloalkyl” as used hereincontemplates an alkyl having one to three halogen substituents.

“Alkylene” refers to an optionally substituted divalent radical which isa branched or unbranched hydrocarbon fragment containing the specifiednumber of carbon atoms, and having two points of attachment. An exampleis propylene [—CH₂CH₂CH₂—, a C₃alkylene].

“Amino” refers to the group —NH₂.

“Aryl” refers to optionally substituted aromatic groups which have atleast one ring having a conjugated pi electron system and includescarbocyclic aryl, and biaryl groups, all of which can be optionallysubstituted. Phenyl and naphthyl groups are preferred carbocyclic arylgroups.

“Aralkyl” or “arylalkyl” refer to alkyl-substituted aryl groups.Examples of aralkyl groups include butylphenyl, propylphenyl,ethylphenyl, methylphenyl, 3,5-dimethylphenyl, tert-butylphenyl.

“Carbamoyl” as used herein contemplates a group of the structure

where in R^(N) is selected from the group consisting of hydrogen, —OH,C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.

“Carbonyl” refers to a group of the structure

“Cycloalkyl” refers to an optionally substituted ring, which can besaturated or unsaturated and monocyclic, bicyclic, or tricyclic formedentirely from carbon atoms. An example of a cycloalkyl group is thecyclopentenyl group (C₅H₇—), which is a five carbon (C₅) unsaturatedcycloalkyl group.

“Heterocycle” refers to an optionally substituted 5- to 7-memberedcycloalkyl ring system containing 1, 2 or 3 heteroatoms, which can bethe same or different, selected from N, O or S, and optionallycontaining one double bond. “Heterocycle” also refers to an optionallysubstituted 4- to 8-membered cycloalkyl ring system containing 1, 2 or 3heteroatoms, which can be the same or different, selected from N, O orS, and optionally containing one double bond.

“Halogen” refers to a chloro, bromo, fluoro or iodo atom radical. Theterm “halogen” also contemplates terms “halo” or “halide.”

“Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen,sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygenand sulfur being particularly preferred heteroatoms in the compounds ofthe present disclosure.

“Heteroaryl” refers to optionally substituted aryl groups having from 1to 9 carbon atoms and the remainder of the atoms are heteroatoms, andincludes those heterocyclic systems described in “Handbook of Chemistryand Physics,” 49th edition, 1968, R. C. Weast, editor; The ChemicalRubber Co., Cleveland, Ohio. See particularly Section C, Rules forNaming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitableheteroaryls include thienyl, pyrryl, furyl, pyridyl, pyrimidyl,pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl,pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl,benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl,benzothiadiazolyl, and the like.

An “optionally substituted” moiety can be substituted with from one tofour, or preferably from one to three, or more preferably one or twonon-hydrogen substituents. Unless otherwise specified, when thesubstituent is on a carbon, it is selected from the group consisting of—OH, —CN, —NO₂, halogen, C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, sulfonyl, sulfonate, sulfonamide and amino, none ofwhich are further substituted. Unless otherwise specified, when thesubstituent is on a carbon, it may also be selected from the groupconsisting of oxo. Unless otherwise specified, when the substituent ison a carbon, it may also be selected from the group consisting ofalkylcarbonyloxy, which is not further substituted. Unless otherwisespecified, when the substituent is on a carbon, it may also be selectedfrom the group consisting of alkylamino, which is not furthersubstituted. Unless otherwise specified, when the substituent is on acarbon, it may also be selected from the group consisting of C₁-C₁₂alkenyl and C₁-C₁₂ alkynyl, neither of which are further substituted.Unless otherwise specified, when the substituent is on a nitrogen, it isselected from the group consisting of C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate andsulfonamide, none of which are further substituted. Unless otherwisespecified, when the substituent is on a nitrogen, it may also beselected from the group consisting of C₁-C₁₂ alkenyl and C₁-C₁₂ alkynyl,neither of which are further substituted.

“Oxo” refers to the ═O substituent.

The term “sulfonamide” as used herein contemplates a group having thestructure

wherein R^(N) is selected from the group consisting of hydrogen, —OH,C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.

The term “sulfonate” as used herein contemplates a group having thestructure

wherein R^(S) is selected from the group consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkanoyl, or C₁-C₁₀alkoxycarbonyl.

“Sulfonyl” as used herein alone or as part of another group, refers toan SO₂ group. The SO₂ moiety is optionally substituted. In particular,“sulfonyl” as used herein contemplates a group having the structure

wherein R^(M) is selected from the group consisting of hydrogen, C₁-C₁₂alkyl, C₁-C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle,aryl, heteroaryl, aralkyl and alkoxy.

Compounds of the present disclosure can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S) depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30, herebyincorporated by reference. The present disclosure contemplates variousstereoisomers and mixtures thereof and are specifically included withinthe scope of the present disclosure. Stereoisomers include enantiomers,diastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of the present disclosure can be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Also, moieties disclosed herein which exist in multiple tautomeric formsinclude all such forms encompassed by a given tautomeric structure.

Individual atoms in the disclosed compounds may be any isotope of thatelement. For example hydrogen may be in the form of deuterium.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans. It can be material which isnot biologically or otherwise undesirable, i.e., the material can beadministered to an individual without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include, forexample, acid addition salts and base addition salts.

“Acid addition salts” according to the present disclosure, are formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

“Base addition salts” according to the present disclosure are formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like. Acceptable inorganicbases include aluminum hydroxide, calcium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature can cause asingle crystal form to dominate.

The term “treating” includes the administration of the compounds oragents of the present invention to a subject to prevent or delay, toalleviate, or to arrest or inhibit development of the symptoms orconditions associated with fatty acid synthase-associated disorders.

A “therapeutically effective amount” or “pharmaceutically effectiveamount” means the amount that, when administered to a subject, produceseffects for which it is administered. For example, a “therapeuticallyeffective amount,” when administered to a subject to inhibit fatty acidsynthase activity, is sufficient to inhibit fatty acid synthaseactivity. A “therapeutically effective amount,” when administered to asubject for treating a disease, is sufficient to effect treatment forthat disease.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryaspect of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat are associated with the targeted or suspected disease or condition.These and other routine methods allow the clinician to select patientsin need of therapy using the methods and formulations of the presentinvention.

Chemical names for the compounds of the present disclosure weregenerated using ChemDraw Ultra version 12.0 (CambridgeSoft Corp.,Cambridge Mass.).

FASN Pathway Modulators

One aspect of the present disclosure includes a method of inhibitingviral infection or treating cancer by contacting a cell with an agentthat modulates the fatty acid synthesis pathway. This method ofinhibiting viral infection or treating cancer can be performed in vitroby contacting virally infected/cancerous cells with an agent thatmodulates the fatty acid synthesis pathway, or in vivo by administeringan agent that modulates the fatty acid synthesis pathway to a subjectinfected with a virus/having cancer. In one aspect, an agent can be aninhibitor of the fatty acid synthesis pathway.

Examples of inhibitors of the fatty acid synthesis pathway that can beused in the methods and compositions of the present disclosure aredescribed below.

In various aspects, the present disclosure provides for compounds ofStructure I:

or pharmaceutically acceptable salts thereof, wherein:

-   L³ is —CH₂—, —CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—,    wherein R⁵⁰ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered    heterocycle;-   n is 1, 2, or 3;-   m is 1 or 2 with the proviso that n+m≧3:-   L-Ar is

-   Ar is

with the proviso that when L-Ar is

Ar is not

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to    6-membered heterocycle; and-   R²² is H, halogen, or C₁-C₂ alkyl.

As noted above, each of the C₁-C₂ alkyl, C₁-C₄ alkyl, C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle and 5- to 6-membered heteroarylmoieties may be optionally substituted. Accordingly, the presentdisclosure provides for compounds of Structure I wherein:

-   -   L³ is —CH₂—, CHR⁵⁰, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—,        wherein R⁵⁰ is optionally substituted C₁-C₆ alkyl, optionally        substituted C₃-C₅ cycloalkyl or optionally substituted 4- to        6-membered heterocycle;    -   n is 1, 2 or 3;    -   m is 1 or 2 with the proviso that n+m≧3;    -   L-Ar is

-   -   Ar is

with the proviso that when L-Ar is

Ar is not

-   -   Het is a optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted C₁-C₄ alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted C₁-C₄ alkyl), wherein when R¹ is not H, —CN or        halogen, R¹ is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C₁-C₄ alkyl,        optionally substituted C₃-C₅ cycloalkyl or an optionally        substituted 4- to 6-membered heterocycle; and    -   R²² is H, halogen or optionally substituted C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure I wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R¹ is H, —CN, —C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl),—O-(4- to 6-membered heterocycle) or —O—(C₁-C₄ alkyl) wherein when R¹ isnot H or —CN, R¹ is optionally substituted with one or more halogens.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R¹ is —CN or C₁-C₂ haloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R¹ is —CN.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R¹ is —Cl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R² is H.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4-to 6-membered heterocycle.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²¹ is C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²² is H or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²² is H.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²² is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²² is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein L³ is —N(CH₃)—.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein n is 2 and m is 2.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein n is 1 or 2.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein n is 1 and m is 2.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² is Hor C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure I wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H or —CH₃.

In various aspects, the present disclosure provides for compounds ofStructure II:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen, or C₁-C₂ alkyl; and-   R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄    alkyl)_(t)—N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl),    —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to 6-membered heterocycle) or —(C₁-C₄    alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:    -   each t is independently 0 or 1; and    -   each R²⁴¹ is independently H or C₁-C₂ alkyl.

As noted above, each of the C₁-C₂ alkyl, C₁-C₄ alkyl, C₃-C₅ cycloalkyl,4- to 6-membered heterocycle and 5- to 6-membered heteroaryl moietiesmay be optionally substituted. Accordingly, the present disclosureprovides for compounds of Structure II wherein:

-   -   L-Ar is

-   -   Ar is

with the proviso that when L-Ar is

Ar is not

-   -   Het is an optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted C₁-C₄ alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted C₁-C₄ alkyl), wherein when R¹ is not H, —CN or        halogen, R¹ is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C₁-C₄ alkyl,        optionally substituted C₃-C₅ cycloalkyl or optionally        substituted 4- to 6-membered heterocycle;    -   R²² is H, halogen or optionally substituted C₁-C₂ alkyl; and    -   R²⁴ is H, optionally substituted C₁-C₄ alkyl, -(optionally        substituted C₁-C₄ alkyl)-OH, -(optionally substituted C₁-C₄        alkyl)_(t)-N(R²⁴¹)₂, -(optionally substituted C₁-C₄        alkyl)_(t)-O_(t)-(optionally substituted C₃-C₅ cycloalkyl),        -(optionally substituted C₁-C₄ alkyl)_(t)-O_(t)-(optionally        substituted 4- to 6-membered heterocycle) or -(optionally        substituted C₁-C₄ alkyl)_(t)-O-(optionally substituted C₁-C₄        alkyl), wherein:        -   t is 0 or 1; and    -   R²⁴¹ is H or optionally substituted C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure II wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure II wherein Ar is

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R¹ is —CN.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R² is H.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4-to 6-membered heterocycle.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is H, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²² is H or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²² is H.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²² is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²² is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄alkyl) wherein t is 0 or 1.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² is Hor C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² is—CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² isH.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H or C₁-C₂alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₃-C₅ cycloalkyl and R²² is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₃-C₅ cycloalkyl and R²² is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂ alkyl) andwherein t is 0 or 1.

In some embodiments, the present disclosure provides for compounds ofStructure II wherein R¹ is —CN and R² is H.

In various aspects, the present disclosure provides for compounds ofStructure III:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen, or C₁-C₂ alkyl;-   R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH,    —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆    cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle)    or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein:    -   t is 0 or 1;    -   u is 0 or 1;    -   with the proviso that when u is 1, t is 1; and    -   each R²⁴¹ is independently H or C₁-C₂ alkyl; and-   R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl or cyclopropyl.

As noted above, each of the C₁-C₂ alkyl (i.e., methyl and ethyl),cyclopropyl, C₁-C₂ alkyl, C₁-C₄ alkyl, C₃-C₅ cycloalkyl, C₃-C₆cycloalkyl, 4- to 6-membered heterocycle and 5- to 6-membered heteroarylmoieties may be optionally substituted. Accordingly, the presentdisclosure provides for compounds of Structure III wherein:

-   -   L-Ar is

-   -   Ar is

-   -   Het is an optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted C₁-C₄ alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted C₁-C₄ alkyl), wherein when R¹ is not H, —CN or        halogen, R¹ is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C₁-C₄ alkyl,        optionally substituted C₃-C₅ cycloalkyl or optionally        substituted 4- to 6-membered heterocycle;    -   R²² is H, halogen or optionally substituted C₁-C₂ alkyl;    -   R²⁴ is H, —CN, -(optionally substituted C₁-C₄ alkyl)-CN,        optionally substituted C₁-C₄ alkyl, -(optionally substituted        C₁-C₄ alkyl)-OH, -(optionally substituted C₁-C₄ alkyl)-N(R²⁴¹)₂,        -(optionally substituted C₁-C₄ alkyl)_(t)-O_(u)-(optionally        substituted C₃-C₆ cycloalkyl), -(optionally substituted C₁-C₄        alkyl)_(t)-O_(u)-(optionally substituted 4- to 6-membered        heterocycle) or -(optionally substituted C₁-C₄        alkyl)-O-(optionally substituted C₁-C₄ alkyl), wherein:        -   t is 0 or 1;        -   u is 0 or 1;        -   with the proviso that when u is 1, t is 1; and        -   R²⁴¹ is H or optionally substituted C₁-C₂ alkyl; and            R²⁵ is halogen, —CN, -(optionally substituted C₁-C₄            alkyl)-CN, optionally substituted methyl, optionally            substituted ethyl or optionally substituted cyclopropyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein when L-Ar is

Ar is not

In some embodiments, the present disclosure provides for compounds ofStructure III wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure III wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure III wherein Ar is

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R¹ is —CN.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R² is H.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₄ alkyl or C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²² is H or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²² is H or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²² is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is H, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl,—(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄ alkyl)-O—(C₁-C₄alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is —(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is —CH₂—O—CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is C₃-C₆ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is —CN or —(C₁-C₂ alkyl)-CN.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is —CN.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is —(C₁-C₂ alkyl)-CN.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is H, —CH₃, —CH₂OH, —CH₂OCH₃, —(CH₂)₂OH,—(CH₂)₂OCH₃ or —(CH₂)₂N(CH₃)₂.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is methyl, isopropyl, cyclopropyl, —CN, or—(C₁-C₂ alkyl)-CN.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is substituted with one or more substituentsselected from C₁-C₂ alkyl, oxo, —CN, halogen, alkanoyl, alkoxycarbonyl,—OH and C₁-C₂ alkoxy.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is substituted with one or more substituentsselected from methyl, —F, methoxy, —C(═O)CH₃ and —C(═O)—OCH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is substituted with two substituents that arethe same or different.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is substituted with three substituents thatare the same or different.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is halogen, —CN, C₁-C₂ alkyl or cyclopropyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is halogen, C₁-C₂ alkyl or cyclopropyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is —CN, —Cl or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is —Cl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is substituted with one or more substituentsselected from —OH, halogen, C₁-C₂ alkyl and alkylcarbonyloxy.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is substituted with one or more substituentsselected from —F, methyl and —O—C(═O)—CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is substituted with two substituents that arethe same or different.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is substituted with three substituents thatare the same or different.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is C₁-C₄ alkyl, —(C₁-C₄ alkyl)-CN or —(C₃-C₆cycloalkyl).

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁴ is —CN, —(C₁-C₂ alkyl)-CN, —(C₃-C₆ cycloalkyl)or methyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is halogen, methyl, ethyl or cyclopropyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²⁵ is halogen, —CN, methyl, ethyl or cyclopropyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₂ alkyl or C₃-C₆ cycloalkyl and R²² isH or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₂ alkyl or C₃-C₆ cycloalkyl, R²² is Hor —CH₃, R²⁴ is —CH₂—O—CH₃ and R²⁵ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is —CH₃ and R²² is H.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R¹ is —CN and R² is H

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₂ alkyl or C₃-C₆ cycloalkyl and R²² isH or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₂ alkyl or C₃-C₆ cycloalkyl, R²² is Hor C₁-C₂ alkyl, R²⁴ is —CH₂—O—CH₃ and R²⁵ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure III wherein R²¹ is C₁-C₂ alkyl and R²² is H.

In various aspects, the present disclosure provides for compounds ofStructure IIIb:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

-   Het is an optionally substituted 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen or C₁-C₂ alkyl; and-   each R²⁴ and R²⁵ is independently H, halogen, —CN, —(C₁-C₄    alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,    —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃—C cycloalkyl), —(C₁-C₄    alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄    alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:    -   each t is independently 0 or 1;    -   each u is independently 0 or 1; and    -   each R²⁴¹ is independently H or C₁-C₂ alkyl,        wherein the compound is not:

As noted above, each of the C₁-C₂ alkyl, C₁-C₄ alkyl, C₃-C₅ cycloalkyl,4- to 6-membered heterocycle and 5- to 6-membered heteroaryl moietiesmay be optionally substituted. Accordingly, the present disclosureprovides for compounds of Structure IIIb wherein:

-   -   L-Ar is

-   -   Ar is

-   -   Het is an optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted C₁-C₄ alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted C₁-C₄ alkyl), wherein when R¹ is not H, —CN or        halogen, R¹ is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C₁-C₄ alkyl,        optionally substituted C₃-C₅ cycloalkyl or optionally        substituted 4- to 6-membered heterocycle;    -   R²² is H, halogen or optionally substituted C₁-C₂ alkyl; and    -   each R²⁴ and R²⁵ is independently H, halogen, —CN, -(optionally        substituted C₁-C₄ alkyl)-CN, optionally substituted C₁-C₄ alkyl,        -(optionally substituted C₁-C₄ alkyl)-OH, -(optionally        substituted C₁-C₄ alkyl)-N(R²⁴¹)₂, -(optionally substituted        C₁-C₄ alkyl)_(t)-O_(u)-(optionally substituted C₃-C₅        cycloalkyl), -(optionally substituted C₁-C₄        alkyl)_(t)-O_(u)-(optionally substituted 4- to 6-membered        heterocycle) or -(optionally substituted C₁-C₄        alkyl)_(t)-O-(optionally substituted C₁-C₄ alkyl), wherein:        -   t is 0 or 1;        -   u is 0 or 1; and        -   R²⁴¹ is H or optionally substituted C₁-C₂ alkyl,        -   wherein the compound is not:

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein when L-Ar is

Ar is not

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein Ar is

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R¹ is —CN.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R² is H.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or4- to 6-membered heterocycle.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²² is H or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²² is H or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²² is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein each R²⁴ and R²⁵ is independently H, —CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein each R²⁴ and R²⁵ is independently H, C₁-C₄ alkyl,—(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is —CN, —Cl, C₁-C₄ alkyl or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄ alkyl)-O—(C₁-C₄alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is —(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is C₁-C₄ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is hydrogen.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is substituted with one or more substituentsselected from halogen, C₃-C₅ cycloalkyl and C₁-C₂ alkoxy.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is substituted with one or more substituentsselected from —F, cyclopropyl and —OCH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is substituted with two substituents that arethe same or different.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is substituted with three substituents thatare the same or different.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is halogen, methyl, ethyl or cyclopropyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is —CN, —Cl, C₁-C₄ alkyl, —(C₁-C₄alkyl)_(t)-O—(C₃-C₅ cycloalkyl) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is —CN, —Cl, —CH₃, —O—(C₃-C₅ cycloalkyl) or—O—(C₁-C₂ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is —CN, —Cl or C₁-C₄ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is —Cl. In some embodiments, the presentdisclosure provides for compounds of Structure IIIb wherein R²⁵ issubstituted with one or more halogen.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is substituted with one or more —F.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is substituted by two substituents.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁵ is substituted by three substituents.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is —CH₃ and R²² is H or methyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² isH or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is —CH₃ and R²² is H.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²⁴ is H or —CH₃ and R²⁵ is —Cl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R¹ is —CN and R² is H.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² isH or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₂ alkyl and R²² is H or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIb wherein R²¹ is C₁-C₂ alkyl and R²² is H.

In various aspects, the present disclosure provides for compounds ofStructure IIIc:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen or C₁-C₂ alkyl; and-   each of R²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen.

As noted above, each of the C₁-C₂ alkyl, C₁-C₄ alkyl, C₃-C₅ cycloalkyl,4- to 6-membered heterocycle and 5- to 6-membered heteroaryl moietiesmay be optionally substituted. Accordingly, the present disclosureprovides for compounds of Structure IIIc wherein:

-   -   L-Ar is

-   -   Ar is

-   -   Het is an optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted C₁-C₄ alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted C₁-C₄ alkyl), wherein when R¹ is not H, —CN or        halogen, R¹ is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C₁-C₄ alkyl,        optionally substituted C₃-C₅ cycloalkyl or optionally        substituted 4- to 6-membered heterocycle;    -   R²² is H, halogen or optionally substituted C₁-C₂ alkyl; and        each of R²⁴ and R²⁵ is independently H, optionally substituted        C₁-C₄ alkyl, or halogen.

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein L-Ar is

Ar is not

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or4- to 6-membered heterocycle.

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein R²¹ is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein R²² is H.

In some embodiments, the present disclosure provides for compounds ofStructure IIIc wherein R²¹ is methyl, R²² is H and L-Ar is

In various aspects, the present disclosure provides for compounds ofStructure IV:

or pharmaceutically acceptable salts thereof, wherein:

-   L-Ar is

-   Ar is

with the proviso that when L-Ar is

Ar is not

-   Het is a 5- to 6-membered heteroaryl;-   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to    6-membered heterocycle) or —O—(C₁-C₄ alkyl), wherein when R¹ is not    H, —CN or halogen, R¹ is optionally substituted with one or more    halogens;-   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;-   R³ is H or F;-   R¹¹ is H or —CH₃;-   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered    heterocycle;-   R²² is H, halogen or C₁-C₂ alkyl; and-   R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂,    —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄    alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄    alkyl)-O—(C₁-C₄ alkyl), wherein:    -   t is 0 or 1;    -   u is 0 or 1;    -   with the proviso that when u is 1, t is 1; and    -   R²⁴¹ is H or C₁-C₂ alkyl.

As noted above, each of the C₁-C₂ alkyl, C₁-C₄ alkyl, C₃-C₅ cycloalkyl,4- to 6-membered heterocycle and 5- to 6-membered heteroaryl moietiesmay be optionally substituted. Accordingly, the present disclosureprovides for compounds of Structure IV wherein:

-   -   L-Ar is

-   -   Ar is

with the proviso that when L-Ar is

Ar is not

-   -   Het is an optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted C₁-C₄ alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted C₁-C₄ alkyl), wherein when R¹ is not H, —CN or        halogen, R¹ is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C₁-C₄ alkyl,        optionally substituted C₃-C₅ cycloalkyl or optionally        substituted 4- to 6-membered heterocycle;    -   R²² is H, halogen or optionally substituted C₁-C₂ alkyl;    -   R²⁴ is H, optionally substituted C₁-C₄ alkyl, -(optionally        substituted C₁-C₄ alkyl)-OH, -(optionally substituted C₁-C₄        alkyl)-N(R²⁴¹)₂, -(optionally substituted C₁-C₄        alkyl)_(t)-O_(u)-(optionally substituted C₃-C₅ cycloalkyl),        -(optionally substituted C₁-C₄ alkyl)_(t)-O_(u)-(optionally        substituted 4- to 6-membered heterocycle) or -(optionally        substituted C₁-C₄ alkyl)-O-(optionally substituted C₁-C₄ alkyl),        wherein:        -   t is 0 or 1;        -   u is 0 or 1;        -   with the proviso that when u is 1, t is 1; and        -   R²⁴¹ is H or optionally substituted C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein L-Ar is

and Ar is

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R¹ is —CN.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R² is H.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4-to 6-membered heterocycle.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is C₃-C₅ cycloalkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²² is H or C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²² is H.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²² is C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²² is —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄ alkyl)-O—(C₁-C₄alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²⁴ is —(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl).

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H or C₁-C₂alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R²¹ is C₃-C₅ cycloalkyl and R²² is H or —CH₃.

In some embodiments, the present disclosure provides for compounds ofStructure IV wherein R¹ is —CN and R² is H.

In various aspects, the present disclosure provides for compounds ofStructure V:

or pharmaceutically acceptable salts thereof, wherein:

-   -   L-Ar is

-   -   Ar is

with the proviso that when L-Ar is

Ar is not

-   -   L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅        cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;    -   Het is a 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl),        —O-(4- to 6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when        R¹ is not H, —CN or halogen, R¹ is optionally substituted with        one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to        6-membered heterocycle;    -   R²² is H, halogen, or C₁-C₂ alkyl; and    -   R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein        R³⁵¹ is C₁-C₆ alkyl, C₃-C₅ cycloalkyl, 4- to 6-membered        heterocycle, aryl or heteroaryl.

As noted above, each of the C₁-C₂ alkyl, C₁-C₄ alkyl, C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, 5- to 6-membered heteroaryl,aryl and heteroaryl moieties may be optionally substituted. Accordingly,the present disclosure provides for compounds of Structure V wherein:

-   -   L-Ar is

-   -   Ar is

with the proviso that when L-Ar is

Ar is not

-   -   L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₅        cycloalkyl, optionally substituted 4- to 6-membered heterocycle,        optionally substituted aryl or optionally substituted        heteroaryl;    -   Het is an optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted C₁-C₄ alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted C₁-C₄ alkyl), wherein when R¹ is not H, —CN or        halogen, R¹ is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C₁-C₄ alkyl,        optionally substituted C₃-C₅ cycloalkyl or optionally        substituted 4- to 6-membered heterocycle;    -   R²² is H, halogen, or optionally substituted C₁-C₂ alkyl; and    -   R³⁵ is —C(O)R³⁵¹, —C(O)NHR³⁵¹, —C(O)OR³⁵¹ or —S(O)₂R³⁵¹, wherein        R³⁵¹ is optionally substituted C₁-C₆ alkyl, optionally        substituted C₃-C₅ cycloalkyl, optionally substituted 4- to        6-membered heterocycle, optionally substituted aryl or        optionally substituted heteroaryl.

In some embodiments, the present disclosure provides for compounds ofStructure V wherein when L-Ar is

Ar is not

In some embodiments, the present disclosure provides for compounds ofStructure V wherein L² is —NHR³⁵.

In some embodiments, the present disclosure provides for compounds ofStructure V wherein L² is —C(O)NHR³⁵¹.

In various aspects, the present disclosure provides for compounds ofStructure VI:

or pharmaceutically acceptable salts thereof, wherein:

-   -   each W, X, Y and Z is independently —N— or —CR²⁶— with the        proviso that not more than 2 of W, X, Y and Z are —N—;    -   each R²⁶ is independently H, C₁-C₄ alkyl, —O—(C₁-C₄ alkyl),        —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄ alkyl);    -   each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄        alkyl and join to form a 3- to 6-membered ring together with the        N to which they are attached and wherein the ring optionally        includes one oxygen atom as one of the members of the ring;    -   Ar is

-   -   Het is a 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, C₁-C₄ alkyl, —O—(C₃-C₅ cycloalkyl),        —O-(4- to 6-membered heterocycle), —O—(C₁-C₄ alkyl) wherein when        R¹ is not H, —CN or halogen, R¹ is optionally substituted with        one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to        6-membered heterocycle; and    -   R²² is H, halogen or C₁-C₂ alkyl.

As noted above, each of the C₁-C₂ alkyl, C₁-C₄ alkyl, C₃-C₅ cycloalkyl,4- to 6-membered heterocycle and 5- to 6-membered heteroaryl moietiesmay be optionally substituted. Accordingly, the present disclosureprovides for compounds of Structure VI wherein:

-   -   each W, X, Y and Z is independently —N— or —CR²⁶— with the        proviso that not more than 2 of W, X, Y and Z are —N—;    -   R²⁶ is H, optionally substituted C₁-C₄ alkyl, —O-(optionally        substituted C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂-(optionally        substituted C₁-C₄ alkyl) or —C(O)-(optionally substituted C₁-C₄        alkyl);    -   each R²⁷ is independently H or optionally substituted C₁-C₄        alkyl or both R²⁷ are optionally substituted C₁-C₄ alkyl and        join to form an optionally substituted 3- to 6-membered ring        together with the N to which they are attached and wherein the        ring optionally includes one oxygen atom as one of the members        of the ring;

Ar is

-   -   Het is an optionally substituted 5- to 6-membered heteroaryl;    -   R¹ is H, —CN, halogen, optionally substituted alkyl,        —O-(optionally substituted C₃-C₅ cycloalkyl), —O-(optionally        substituted 4- to 6-membered heterocycle) or —O-(optionally        substituted alkyl), wherein when R¹ is not H, —CN or halogen, R¹        is optionally substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or optionally        substituted C alkyl;    -   R³ is H or F;    -   R¹¹ is H or —CH₃;    -   R²¹ is H, halogen, optionally substituted C alkyl, optionally        substituted C₃-C₅ cycloalkyl or an optionally substituted 4- to        6-membered heterocycle; and    -   R²² is H, halogen or optionally substituted C₁-C₂ alkyl.

In some embodiments, the present disclosure provides for compounds ofStructure VI wherein Ar is

In some embodiments, the present disclosure provides for compounds ofStructure VI wherein Y is —CR²⁶— wherein R²⁶ is —N(R²⁷)₂.

In some embodiments, the present disclosure provides for compounds ofStructure VI wherein X is —N—.

Synthesis of Compounds

Also described herein are methods of synthesizing the compounds of thepresent disclosure. Compounds of the present disclosure can besynthesized according to the synthetic schemes provided below.

Scheme 1 provides methods useful for synthesizing the L moiety ofStructures I-IV. In Scheme 1, each of m′ and n′ are independently 1 or2. Ar is as defined in Structures I-V.

Scheme 2 provides methods useful for preparing the

moiety in each of Structures I-IV.

Scheme 2

Schemes 3-5 provide methods useful in the synthesis of compounds ofStructure III.

Scheme 3

Scheme 5

Schemes 6-7 provide methods useful in the synthesis of compounds ofStructure II.

Scheme 6

Scheme 7

Scheme 8 provides methods useful in the synthesis of compounds ofStructure IIIb.

Scheme 8

Scheme 9 provides methods useful in the synthesis of compounds ofStructure I.

Scheme 9

Additional methods for producing particular compounds according to thepresent disclosure are provided in the Examples. One skilled in the artwill recognize that other compounds of structures can be made bymodifications to the specifically disclosed schemes employing methodsknown to those of skill in the art. Additional examples can be found inTABLE 26.

Many such techniques are well known in the art. However, many of theknown techniques are elaborated in Compendium of Organic SyntheticMethods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3, 1977; Vol. 4, 1980; Vol. 5,1984; and Vol. 6 as well as March in Advanced Organic Chemistry (1985);Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes (1993); Advanced OrganicChemistry Part B: Reactions and Synthesis, Second Edition (1983);Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, SecondEdition (1977); Protecting Groups in Organic Synthesis, Second Edition;and Comprehensive Organic Transformations (1999).

Antiviral Methods of Treatment

In various aspects, the present disclosure provides methods for treatingviral infection in a subject, the method comprising administering to asubject in need of such treatment an effective amount of a compound ofStructures I, II, III, IIIb, IIIc, IV, V and VI or as provided in TABLE26.

In various aspects, the disclosure provides methods for treating a viralinfection, the method comprising administering the compounds of thepresent disclosure to a subject in need thereof the agent.

In various aspects, the present disclosure provides methods for treatinghepatitis C infection by administering to the subject one or morecompounds disclosed herein.

In certain aspects the compounds of the present disclosure may be usedin combination with other antiviral treatments in the treating of viralinfection.

In various aspects the compounds of the present disclosure can be usedfor the treatment of infection of an animal subject, such as a human.

Anticancer Activity

In various aspects, the present disclosure provides methods for treatingcancer in subject, the method comprising administering to a subject inneed of such treatment an effective amount of a compound of StructuresI, II, III, IIIb, IIIc, IV, V and VI or as provided in TABLE 26. Infurther aspects, compounds having Structures I, II, III, IIIb, IIIc, IV,V and VI or as provided in TABLE 26 can be used for the manufacture of amedicament for treating cancer.

In certain aspects, the present disclosure provides a method forinhibiting tumor cell growth in a subject, the method comprisingadministering to a subject in need of such treatment an effective amountof a compound of Structure I, II, III, IIIb, IIIc, IV, V and VI or asprovided in TABLE 26. In further aspects, the tumor can be derived frombreast, lung, thyroid, lymph node, kidney, ureter, bladder, ovary,teste, prostate, bone, skeletal muscle, bone marrow, stomach, esophagus,small bowel, colon, rectum, pancreas, liver, smooth muscle, brain,spinal cord, nerves, ear, eye, nasopharynx, oropharynx, salivary gland,or heart tissue. In certain aspects, the present compounds can beadministered concurrently with one or more additional anti-cancertreatments.

In certain aspects, the present disclosure provides a method fortreating pancreatic cancer in a subject, the method comprisingadministering to a subject in need of such treatment an effective amountof a compound of Structure I, II, III, IIIb, IIIc, IV, V and VI or asprovided in TABLE 26.

In certain aspects, the present disclosure provides for a method oftreating colon cancer in a subject, the method comprising administeringto a subject in need of such treatment an effective amount of a compoundof Structure I, II, III, IIIb, IIIc, IV, V and VI or as provided inTABLE 26.

Rapidly proliferating cancer cells activate the fatty acid synthesispathway to supply the high levels of lipids needed for membrane assemblyand oxidative metabolism. (Flavin, R. et al. (2010) Future Oncology.6(4):551-562) Inhibitors of fatty acid synthesis have demonstrated invivo activity in preclinical cancer models. (Orita, H. et al. (2007)Clinical Cancer Research. 13(23):7139-7145 and Puig, T. et al. (2011)Breast Cancer Research, 13(6):R131) Additionally, fatty acid synthesissupports new blood vessel formation and inhibitors of this pathway haveactivity in in vitro models of angiogenesis. (Browne, C. D., et al.(2006) The FASEB Journal, 20(12):2027-2035).

Utility in Metabolic Disorders

In various aspects, the compounds of the present disclosure have utilityin the treating of metabolic diseases. FASN has been demonstrated to beinvolved in regulation of glucose, lipids and cholesterol metabolism.Mice with a liver-specific inactivation of FASN have normal physiologyunless fed a zero-fat diet, in which case they develop hypoglycemia andfatty liver, both of which are reversed with dietary fat. (Chakravarthy,M. V., et al. (2005) Cell Metabolism 1:309-322). Db/+ mice fed a highfructose diet exhibit reduced liver triglyceride levels and improvedinsulin sensitivity when treated for 28 days with platensimycin, acovealent inhibitor of FASN. (Wu, M. et al. (2011) PNAS108(13):5378-5383). Ambient glucose levels are also reduced in db/dbmice following treatment with platensimycin. These results provideevidence that inhibiting FASN can yield therapeutically relevantbenefits in animal models of diabetes and related metabolic disorders.Thus the disclosed FASN inhibitors are useful in the treatment ofdisorders characterized by disregulation in these systems. Withoutlimitation, examples include steatosis and diabetes.

Pharmaceutical Compositions, Formulations, Routes of Administration, andEffective Doses

Also provided herein are pharmaceutical compositions comprising thecompounds of the present disclosure.

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Structures I, II,III, IIIb, IIIc, IV, V and VI and a pharmaceutically acceptable carrier,excipient, or diluent.

In certain aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of TABLE 26 and apharmaceutically acceptable carrier, excipient, or diluent.

Yet another aspect of the present invention relates to formulations,routes of administration and effective doses for pharmaceuticalcompositions comprising an agent or combination of agents of the instantinvention. Such pharmaceutical compositions can be used to treat viralinfections as described above.

Compounds of the invention can be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, transdermal patch, pulmonary,vaginal, suppository, or parenteral (including intramuscular,intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneousand intravenous) administration or in a form suitable for administrationby aerosolization, inhalation or insufflation. General information ondrug delivery systems can be found in Ansel et al., PharmaceuticalDosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins,Baltimore Md. (1999).

In various aspects, the pharmaceutical composition includes carriers andexcipients (including but not limited to buffers, carbohydrates,mannitol, proteins, polypeptides or amino acids such as glycine,antioxidants, bacteriostats, chelating agents, suspending agents,thickening agents and/or preservatives), water, oils including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like, saline solutions,aqueous dextrose and glycerol solutions, flavoring agents, coloringagents, detackifiers and other acceptable additives, adjuvants, orbinders, other pharmaceutically acceptable auxiliary substances asrequired to approximate physiological conditions, such as pH bufferingagents, tonicity adjusting agents, emulsifying agents, wetting agentsand the like. Examples of excipients include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. In another aspect, thepharmaceutical preparation is substantially free of preservatives. Inanother aspect, the pharmaceutical preparation can contain at least onepreservative. General methodology on pharmaceutical dosage forms isfound in Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It willbe recognized that, while any suitable carrier known to those ofordinary skill in the art can be employed to administer the compositionsof this invention, the type of carrier will vary depending on the modeof administration.

Compounds can also be encapsulated within liposomes using well-knowntechnology. Biodegradable microspheres can also be employed as carriersfor the pharmaceutical compositions of this invention. Suitablebiodegradable microspheres are disclosed, for example, in U.S. Pat. Nos.4,897,268; 5,075,109; 5,928,647; 5,811,128; 5,820,883; 5,853,763;5,814,344 and 5,942,252.

The compound can be administered in liposomes or microspheres (ormicroparticles). Methods for preparing liposomes and microspheres foradministration to a patient are well known to those of skill in the art.U.S. Pat. No. 4,789,734, the contents of which are hereby incorporatedby reference, describes methods for encapsulating biological materialsin liposomes. Essentially, the material is dissolved in an aqueoussolution, the appropriate phospholipids and lipids added, along withsurfactants if required, and the material dialyzed or sonicated, asnecessary. A review of known methods is provided by G. Gregoriadis,Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp.2.sup.87-341 (Academic Press, 1979).

Microspheres formed of polymers or proteins are well known to thoseskilled in the art, and can be tailored for passage through thegastrointestinal tract directly into the blood stream. Alternatively,the compound can be incorporated and the microspheres, or composite ofmicrospheres, implanted for slow release over a period of time rangingfrom days to months. See, for example, U.S. Pat. Nos. 4,906,474,4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contentsof which are hereby incorporated by reference.

The concentration of drug can be adjusted, the pH of the solutionbuffered and the isotonicity adjusted to be compatible with intravenousinjection, as is well known in the art.

The compounds of the invention can be formulated as a sterile solutionor suspension, in suitable vehicles, well known in the art. Thepharmaceutical compositions can be sterilized by conventional,well-known sterilization techniques, or can be sterile filtered. Theresulting aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterilesolution prior to administration. Suitable formulations and additionalcarriers are described in Remington The Science and Practice of Pharmacy(20^(th) Ed., Lippincott Williams & Wilkins, Baltimore Md.), theteachings of which are incorporated by reference in their entiretyherein.

Typical salts are those of the inorganic ions, such as, for example,sodium, potassium, calcium, magnesium ions, and the like. Such saltsinclude salts with inorganic or organic acids, such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, mandelic acid, malic acid, citric acid,tartaric acid or maleic acid. In addition, if the agent(s) contain acarboxy group or other acidic group, it can be converted into apharmaceutically acceptable addition salt with inorganic or organicbases. Examples of suitable bases include sodium hydroxide, potassiumhydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine,diethanolamine, triethanolamine, and the like.

The agent(s) (or pharmaceutically acceptable salts can be administeredper se or in the form of a pharmaceutical composition wherein the activeagent(s) is in an admixture or mixture with one or more pharmaceuticallyacceptable carriers.

EXAMPLES Example 1 Synthesis of Compounds of the Present Disclosure

General:

All reactions and manipulations described were carried out in wellventilated fume-hoods. Operations and reactions carried out at elevatedor reduced pressure were carried out behind blast shields.Abbreviations: ACN, acetonitrile; AcOH, acetic acid; AIBN,azobisisobutyronitrile; BF₃-Et₂O, boron trifluoride diethyl etherate;(Boc)₂O, di-tert-butyl dicarbonate; BuLi, butyl lithium; CDI,1,1′-Carbonyldiimidazole; DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCE,1,2-dichloroethane; DCM, dichloromethane or methylene chloride; DIEA,N,N-Diisopropylethylamine; DMA, N,N-dimethylacetamide; DMAP,4-dimethylaminopyridine; DME, 1,2-dimethoxyethane;DMEDA—N,N′-dimethylethylenediamine; DMF, N,N-dimethylformamide; DMSO,dimethylsulfoxide; DPPP, 1,3-bis(diphenylphosphino)propane; EDC,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EtOAc,ethyl acetate; EtOH, Ethanol; HATU,2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate; HBTU,0-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate or2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate; HMPA, hexamethylphosphoramide; HOAc, acetic acid;HOBT, 1-Hydroxybenzotriazole; LDA, lithium diisopropylamine; m-CPBA,3-chloroperbenzoic acid; MeOH, methanol; MSCl, methanesulfonyl chloride;MsOH, methanesulfonic acid; NaHMDS, sodium hexamethyldisilazane, NBS,N-bromosuccinimide; NCS, N-chlorosuccinimide; NIS, N-iodosuccinimide;Pd(dppf)Cl₂,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE,petroleum ether; PPA, polyphosporic acid; PTAT, phenyltrimethylammoniumtribromide; PTSA, p-toluenesulfonic acid; Py, pyridine; Pyr, pyridine;TBAF, tetrabutylammonium fluoride; TEA, triethylamine; TFA,trifluoroacetic acid; TFAA, trifluoroacetic anhydride; THF,tetrahydrofuran; TMSCl, chlorotrimethylsilane; TMSCN, trimethylsilylcyanide; TsOH, p-toluenesulfonic acid.

Compound 1.1. tert-Butyl 4-(4-cyanophenyl)piperidine-1-carboxylate

Into a 500-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a suspensionof Zn (21.6 g, 330 mmol) in DMA (53 mL). A 7:5 v/v mixture ofTMSCl/1,2-dibromoethane (5.8 mL) was added to the mixture drop-wise at arate to maintain the temperature below 65° C. The mixture was stirredfor an additional 10 min, then a solution of tert-butyl4-iodopiperidine-1-carboxylate (68.7 g, 220 mmol) in DMA (122 mL) wasadded drop-wise at 40-45° C. and the mixture was stirred at the sametemperature for 30 min. The mixture was cooled to room temperature andstirring was ceased to allow for the zinc powder to settle. Into another500-mL round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a mixture of 4-bromobenzonitrile (20g, 110 mmol), CuI (2.1 g, 11 mmol), Pd(dppf)Cl₂ (4.51 g, 5.5 mmol) andDMA (100 mL). The freshly prepared zinc reagent solution was decantedinto an addition funnel and added drop-wise to the mixture at roomtemperature. The resulting mixture was stirred at 85° C. for 4 h, thencooled to 20° C. and diluted with methyl tert-butyl ether (500 mL) andcarefully quenched with 1 M ammonium chloride (500 mL). The mixture wasstirred at room temperature for 30 min and then filtered to removesolids. The organic layer was washed with saturated aqueous ammoniumchloride (100 mL), followed by brine (3×100 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:10) as the eluent to yield the title compound as a brown oil (20 g,crude) and used in the next step without additional purification.

Compound 1.2. 4-(Piperidin-4-yl)benzonitrile hydrochloride

Into a 500-mL three neck round-bottom flask, was placed a solution oftert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1, 20g, crude) in ethyl acetate (200 mL). Hydrogen chloride (gas) wasintroduced to the solution and the resulting mixture was stirred for 30min at room temperature. The solids were collected by filtration, thenwashed with ethyl acetate (100 mL) and ether (100 mL) to yield the titlecompound as a white solid (14 g, 57% over two steps).

Compound 1.3. 5-Iodo-2,4-dimethylbenzoic acid

A solution of 2,4-dimethylbenzoic acid (20.0 g, 133 mmol), sodiumperiodate (14.27 g, 66.72 mmol), iodine (37.25 g, 146.8 mmol), andsulfuric acid (1.96 g, 20.0 mmol) in acetic acid (150 mL) was stirred at110° C. for 6 h. The mixture was allowed to cool to ambient temperaturethen carefully diluted into water (1.2 L). To this mixture was carefullyadded saturated aqueous Na₂S₂O₃ (800 mL). The resulting solids werecollected by filtration, then dissolved in ethyl acetate (1.2 L) andwashed with saturated aqueous Na₂S₂O₃ (300 mL) followed by brine (400mL). The organic layer was dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The crude residue was re-crystallized fromethanol:H₂O (2:1) to yield the title compound as a white solid (30 g,82%).

Compound 1.4. 2,4-Dimethyl-5-propionylbenzoic acid

Into a 100-mL autoclave (30 atm), was placed a solution of5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 2.00 g, 7.24 mmol) inethylene glycol dimethyl ether (20 mL). Triphenylphosphine (190 mg, 0.73mmol), Pd(PPh₃)₂Cl₂ (500 mg, 0.71 mmol) and diethylaluminum chloride(2M, 10.8 mL, 21.6 mmol) were added to the reaction mixture. Theresulting mixture was stirred under pressure with carbon monoxide (gas,30 atm) at 80° C. for 15 h. (CAUTION: Highly toxic gas at high pressure.All necessary safety precautions were performed). After cooling to roomtemperature, the mixture was carefully purged, then quenched with 20 mLof water. Aqueous HCl (2M) was added carefully to adjust the pH to 5-6and the aqueous layer was extracted with ethyl acetate (100 mL). Thecombined organic layers were washed with brine (2×100 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1:40-1:20) as the eluent to yield the titlecompound as a light yellow solid (1.2 g, 80%).

Compound 1.5. Methyl 2,4-dimethyl-5-propionylbenzoate

To a 100-mL round-bottom flask, was carefully added2,4-dimethyl-5-propionylbenzoic acid (compound 1.4, 1.2 g, 5.8 mmol),sulfuric acid (1.0 mL, 19 mmol) and methanol (30 mL). The resultingsolution was stirred at 70° C. for 5 h, then concentrated under reducedpressure. The residue was carefully diluted with H₂O (50 mL) andextracted ethyl acetate (100 mL). The organic layer was washed with H₂O(2×100 mL) and brine (100 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel columnchromatography with ethyl acetate/petroleum ether (1:100) asthe eluent to yield the title compound as a light yellow solid (0.90 g,70%).

Compound 1.6. Methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl2,4-dimethyl-5-propionylbenzoate (compound 1.5, 600 mg, 2.72 mmol) inchloroform (20 mL). Bromine (154 μL, 3.00 mmol) was added and theresulting solution was stirred at 20° C. for 2 h. The mixture wasconcentrated under reduced pressure to yield the title compound as ayellow oil (1.0 g, crude), which was used in the next step withoutfurther purification.

Compound 1.7. Methyl5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a round-bottom flask, was placed a solution of methyl5-(2-bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 400 mg, 1.34mmol) in acetonitrile (30 mL). Acetimidamide hydrochloride (260 mg, 2.75mmol) and potassium carbonate (550 mg, 3.99 mmol) were added and theresulting mixture was stirred at 80° C. for 15 h. After cooling to roomtemperature, the mixture was concentrated under reduced pressure and theresidue was diluted with ethyl acetate (50 mL) and washed with brine(2×25 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith ethyl acetate/petroleum ether (1:1) to ethyl acetate as the eluentto yield the title compound as a yellow oil (0.20 g, 58%).

Compound 1.8. 5-(2,4-Dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

Into a 50-mL round-bottom flask, were placed methyl5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 1.7,300 mg, 1.16 mmol) and sodium hydroxide (465 mg, 11.6 mmol) in methanol(20 mL) and H₂O (5 mL). The resulting solution was stirred at 55° C. for4 h, then after cooling to room temperature, aqueous HCl (2 M) was addedto adjust the pH to 5. The resulting mixture was concentrated underreduced pressure and the residue was dissolved in methanol (5 mL). Thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure to yield the title compound as a light yellowsolid (280 mg, crude), which was used in the next step without furtherpurification.

Compound 1.4-(1-(5-(2,4-Dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

A mixture of 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 1.8, 280 mg, 1.15 mmol), EDC.HCl (330 mg, 1.72 mmol),4-dimethylaminopyridine (420 mg, 3.44 mmol), and HOBT (180 mg, 1.33mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature.After 5 min, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2,230 mg, 1.03 mmol) was added and the resulting solution was stirred atroom temperature for 15 h, then quenched with ice water (20 mL). Theaqueous was extracted with ethyl acetate (50 mL) and the combinedorganics was washed with brine (2×50 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 0.05% TFA and CH₃CN (22% CH₃CN up to 37% in 7 min, up to 100%in 2 min, down to 22% in 1 min); Detector, Waters 2489, 254 & 220 nm.The fractions containing pure compound were combined and lyophilized toyield the title compound as a white solid (214 mg, 50%). m/z (ES+) 413(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.68 (d, J=7.8 Hz, 2H), 7.47 (d,J=8.4 Hz, 2H), 7.36 (br s, 1H), 7.27 & 7.16 (2 singlets, rotamers, Ar—H,1H), 4.9-4.82 (m, 1H partially obscured by water peak), 3.72-3.55 (m,1H), 3.35-3.20 (m, 1H partially overlapped with methanol solvent peak),3.08-2.92 (m, 2H), 2.65 (s, 3H), 2.44 & 2.34 (2 singlets, rotamers,Ar—CH₃, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.10-1.96 (m, 1H), 1.93-1.53(m, 3H).

Compounds 2.1 and 2.2. Methyl5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate andmethyl 5-(2-(methoxymethyl)-4-methyloxazol-5-yl)-2,4-dimethylbenzoate

Into a 100-mL round-bottom flask, was placed a mixture of methyl5-(2-bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 600 mg, 2.01mmol), 2-methoxyethanimidamide hydrochloride (510 mg, 4.09 mmol),potassium carbonate (840 mg, 6.08 mmol) and acetonitrile (30 mL). Theresulting mixture was stirred at 80° C. overnight, then cooled to roomtemperature and concentrated under reduced pressure. The residue wasdiluted with H₂O (50 mL) and extracted with ethyl acetate (100 mL). Theorganics was washed brine (2×50 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1:2) as theeluent to yield methyl5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 2.1) (0.11 g, 19%) and methyl5-(2-(methoxymethyl)-4-methyloxazol-5-yl)-2,4-dimethylbenzoate (compound2.2) (0.30 g, 52%), both as a yellow oils.

Compound 2.3.5-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

Into a 50-mL round-bottom flask, was placed a solution of methyl5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 2.1, 150 mg, 0.52 mmol) in methanol (15 mL) and H₂O (5 mL).Sodium hydroxide (280 mg, 7.00 mmol) was added and the resultingsolution was stirred at 40° C. for 15 h. After cooled to roomtemperature, the solution was adjusted to pH 5 with aqueous HCl (2 M)and the resulting mixture was concentrated under reduced pressure. Theresidue was dissolved in methanol (5 mL) and the solids were filteredoff. The filtrate was concentrated under reduced pressure to yield thetitle compound as a light yellow solid (140 mg, crude), which was usedin the next step without further purification.

Compound 2.4-(1-(5-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

A mixture of5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 2.3, 140 mg, 0.51 mmol), EDC.HCl (150 mg, 0.78 mmol),4-dimethylaminopyridine (190 mg, 1.56 mmol), and HOBT (80 mg, 0.59 mmol)in N,N-dimethylformamide (6 mL). The mixture was stirred at roomtemperature, then after 15 min, 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.2, 100 mg, 0.45 mmol) was added. The resultingsolution was stirred for 15 h at room temperature, then quenched with 20mL of H₂O. The aqueous was extracted with ethyl acetate (40 mL) and thecombined organics was washed with brine (2×30 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, Sum,19*150 mm; mobile phase, water with 0.05% TFA and CH₃CN (23% CH₃CN up to38% in 7 min, up to 100% in 2 min, down to 23% in 1 min); Detector,Waters 2489, 254 &220 nm. The fractions containing pure compound werecombined and lyophilized to yield the title compound as a white solid(70.4 mg, 35%).

Compound 3.4-(1-(5-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

Into a 50-mL 3-necked round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a mixture of4-(1-(5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 2, 30 mg, 0.068 mmol), NaI (20 mg, 0.13 mmol), 15-crown-5 (30mg, 0.14 mmol) and dichloromethane (10 mL). The mixture was cooled to−30° C. and boron tribromide (70 mg, 0.28 mmol) was added. The resultingmixture was allowed to warm to room temperature and stirred for 15 h.The reaction mixture was carefully quenched by the addition of saturatedaqueous sodium bicarbonate (10 mL) and the resulting mixture wasextracted dichloromethane (2×20 mL). The combined organics was washedwith saturated aqueous Na₂S₂O₃ (2×20 mL), then dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The crude product was purifiedby Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18 OBD Column, Sum, 19*150 mm; mobile phase, waterwith 0.05% TFA and CH₃CN (21% CH₃CN up to 35% in 8 min, up to 100% in 2min, down to 21% in 1 min); Detector, Waters 2489, 254&220 nm. Thefractions containing pure compound were combined and lyophilized toyield the title compound as a white solid (5.0 mg, 17%). m/z (ES+) 429(M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.74-7.65 (m, 2), 7.48 (d, J=8.0 Hz,2H), 7.38 (d, J=5.6 Hz, 1H), 7.29 & 7.16 (2 singlets, rotamers, Ar—H,1H), 4.9 (1H obscured by water peak), 3.64 (app t, J=15.0 Hz, 1H),3.35-3.21 (m, 1H partially overlapped with methanol solvent peak),3.09-2.93 (m, 1H), 2.45 & 2.34 (2 singlets, rotamers, Ar—CH₃, 3H), 2.29(s, 3H), 2.24 (s, 3H), 2.09-1.97 (m, 1H), 1.92-1.71 (m, 2H), 1.70-1.55(m, 1H).

Compound 4.1. 3-Formyl-4-methylbenzoic acid

To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.0mmol) in tetrahydrofuran (30 mL) under nitrogen at −78° C. was addedn-BuLi (10 mL, 2.5 M in THF, 25 mmol) drop-wise. The mixture was stirredfor 1 h below −70° C., then DMF (5 mL) was slowly added. The resultingsolution was slowly warmed to room temperature and stirred for 1 h, thencarefully quenched by slow addition of water (50 mL). The pH wasadjusted to 3-4 using aqueous HCl (6 M) and the resulting mixture wasextracted with ethyl acetate (2×50 mL). The combined organics was dried(Na₂SO₄), filtered, and concentrated under reduced pressure to yield thetitle compound as a yellow solid (1.6 g, 98%).

Compound 4.2. 3-(1-Hydroxybut-3-en-1-yl)-4-methylbenzoic acid

Into a 100-mL 3-necked round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 3-formyl-4-methylbenzoic acid (compound 4.1, 2.00 g, 12.2 mmol) intetrahydrofuran (50 mL). The mixture was cooled to −10 to 0° C. thenallylmagnesium bromide (1M in Et₂O, 24.4 mL, 24.4 mmol) was addeddrop-wise. The resulting mixture was stirred for 1 hr at −10-0° C., thencarefully quenched with saturated aqueous NH₄Cl (50 mL) and diluted withethyl acetate (200 mL). The organic layer was washed with saturatedaqueous NH₄Cl (80 mL) and brine (2×80 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield the title compound as alight red solid (2.4 g, crude), which was used in the next step withoutfurther purification.

Compound 4.3. Methyl 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoate

Into a 100-mL round-bottom flask, was added a solution of3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoic acid (compound 4.2, 1.4 g,6.79 mmol) in N,N-dimethylformamide (20 mL). Sodium bicarbonate (1.14 g,13.6 mmol) and methyl iodide (0.847 mL, 13.6 mmol) were added and theresulting mixture was stirred overnight at 25° C. The reaction wasquenched with saturated aqueous Na₂S₂O₃ (50 mL) and diluted with EtOAc(150 mL). The organic layer was washed with brine (3×50 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography with ethyl acetate/petroleumether (1:3) as the eluent to yield the title compound as a light yellowoil (800 mg, 53%).

Compound 4.4. Methyl 3-(2-cyclopropyl-1-hydroxyethyl)-4-methylbenzoate

Into a 100-mL 3-necked round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof methyl 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoate (compound 4.3, 50mg, 0.23 mmol). Diethylzinc (1 M in toluene) (3.45 mL, 3.45 mmol) intoluene (10 mL) was added and the mixture was cooled to 0-5° C., thendiiodomethane (924 mg, 3.45 mmol) was added drop-wise. The resultingmixture was stirred for 2 h at room temperature, then carefully quenchedwith 1 M aqueous HCl (50 mL) and diluted with MTBE (50 mL). The aqueousphase was extracted with MTBE (3×20 mL) and the combined organics waswashed with saturated sodium bicarbonate (2×20 mL), brine (2×20 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:3) as the eluent to yield the title compoundas a yellow oil (40 mg, 74%).

Compound 4.5. Methyl 3-(2-cyclopropylacetyl)-4-methylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl3-(2-cyclopropyl-1-hydroxyethyl)-4-methylbenzoate (compound 4.4, 200 mg,0.85 mmol) in dichloromethane (30 mL). This was followed by the additionof Dess-Martin periodinane (721 mg, 1.70 mmol) in portions at roomtemperature. The resulting solution was stirred for 1 h at roomtemperature, then quenched with saturated aqueous Na₂S₂O₃ (30 mL). Theresulting mixture was extracted with DCM (3×20 mL) and the combinedorganics was washed with brine (2×20 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1:5) as theeluent to yield the title compound as a yellow oil (150 mg, 75%).

Compound 4.6. Methyl 3-(2-bromo-2-cyclopropylacetyl)-4-methylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl3-(2-cyclopropylacetyl)-4-methylbenzoate (compound 4.5, 150 mg, 0.65mmol) in chloroform (15 mL). Bromine (40 μL, 0.78 mmol) in chloroform (2mL) was added drop-wise to the reaction mixture. The resulting solutionwas stirred for 2 h at room temperature, then concentrated under reducedpressure to yield the title compound as a yellow oil (200 mg, crude),which was used in the next step without further purification.

Compound 4.7. 2-Methoxyacetimidamide hydrochloride

Into a 250-mL round-bottom flask, was placed a solution of2-methoxyacetonitrile (6.00 g, 84.4 mmol) in methanol (60 mL). Sodiummethoxide (860 mg, 15.9 mmol) was added and the mixture was stirred atroom temperature for 40 h. Ammonium chloride (4.52 g, 84.5 mmol) wasthen added and the mixture was stirred at 40° C. for 12 h thenconcentrated under reduced pressure. The residue was diluted with H₂O(20 mL) and washed with ethyl acetate (2×20 mL). The aqueous wasconcentrated under reduced pressure to yield the title compound as ayellow solid (5 g, crude), which was used in the next step withoutfurther purification.

Compound 4.8 and compound 4.9. Methyl3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoateand methyl3-(4-cyclopropyl-2-(methoxymethyl)oxazol-5-yl)-4-methylbenzoate

Into a 100-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was placed methyl3-(2-bromo-2-cyclopropylacetyl)-4-methylbenzoate (compound 4.6, 150 mg,0.48 mmol), 2-methoxyacetimidamide hydrochloride (compound 4.7, 90 mg,0.72 mmol), potassium carbonate (200 mg, 1.44 mmol), andN,N-dimethylformamide (15 mL). The resulting mixture was stirred at 80°C. for 3 h, then diluted with ethyl acetate (100 mL). The mixture waswashed with brine (3×30 mL) and water (3×30 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:2) as the eluent to yield methyl3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 4.8) (30 mg, 21%) and methyl3-(4-cyclopropyl-2-(methoxymethyl)oxazol-5-yl)-4-methylbenzoate(compound 4.9) (60 mg, 41%), both as a yellow oils.

Compound 4.10.3-(4-Cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid

Into a round-bottom flask, was placed a solution of methyl3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 4.8, 35 mg, 0.12 mmol) in methanol (5 mL), a solution ofsodium hydroxide (9.6 mg, 0.24 mmol) in water (0.3 mL) was added to thereaction mixture. The resulting solution was stirred for 2 h at roomtemperature, then diluted with water (5 mL). Aqueous HCl (6 M) wascarefully added to adjust the pH to 1-2 and the mixture was extractedwith dichloromethane (4×10 mL). The combined organics were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to yield thetitle compound as a yellow oil (30 mg, crude), which was used in thenext step without further purification.

Compound 4.4-(1-(3-(4-Cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

Into a round-bottom flask, was placed a solution of3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 4.10, 30 mg, 0.10 mmol) in dichloromethane (5 mL). HBTU(76 mg, 0.20 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2, 35 mg, 0.15 mmol, 1.50 equiv) and triethylamine (28 μL,0.20 mmol) were added and the mixture was stirred overnight at roomtemperature. The mixture was diluted with DCM (30 mL) and washed withwater (3×15 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire PrepC18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA andCH₃CN (25.0% CH₃CN up to 38.0% in 7 min, up to 100.0% in 3 min, down to25.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractionscontaining pure compound were combined and lyophilized to yield thetitle compound as a white solid (5.9 mg, 12%). m/z (ES+) 455 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃): δ 7.69 (d, J=8.0 Hz, 2H), 7.59-7.53 (m, 2H),7.53-7.47 (m, 3H), ˜4.9-4.75 (m, 1H partially obscured by water peak),4.72 (s, 2H), 3.99-3.85 (m, 1H), 3.52 (s, 3H), ˜3.3 (m, 1H overlappedwith methanol solvent peak), 3.08-2.93 (m, 2H), 2.37 (s, 3H), 2.08-1.93(m, 1H), 1.93-1.65 (m, 4H), 1.02-0.94 (m, 2H), 0.74-0.68 (m, 2H).

Compound 5.1. tert-Butyl 3-(4-cyanophenyl)azetidine-1-carboxylate

A modified procedure to that described in Org. Lett. 2008, 10, 3259 wasperformed as follows. To a 20-mL vial was added (4-cyanophenyl)boronicacid (1.01 g, 6.87 mmol), trans-2-aminocyclohexanol hydrochloride (32mg, 0.21 mmol), nickel (II) iodide (66 mg, 0.21 mmol) and sodiumhexamethyldisilazane (1.29 g, 7.06 mmol). The system was purged withnitrogen and charged with isopropyl alcohol (7 mL). The mixture wasstirred at room temperature for 10 minutes then sonicated for 1 min.While stirring, tert-butyl 3-iodoazetidine-1-carboxylate (1.00 g, 3.53mmol) was added and the syringe rinsed with isopropyl alcohol (2×500μL). The suspension was stirred at 80° C. for 1 hour then concentratedunder reduced pressure. The residue was purified by silica gelchromatography (hexanes to 25% ethyl acetate) to yield the titlecompound as a pale yellow oil which solidified upon standing (0.832 g,46%). m/z (ES+) 203 (M-C₄H₈+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.65 (d withfine str., J=8.4 Hz, 2H), 7.43 (d with fine str., J=8.4 Hz, 2H), 4.37(app t, J=8.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.81-7.73 (m, 1H).

Compound 5.2. 4-(Azetidin-3-yl)benzonitrile hydrochloride

tert-Butyl 3-(4-cyanophenyl)azetidine-1-carboxylate (compound 5.1, 100mg, 0.387 mmol) was added to a 4-mL vial. HCl in dioxane (4 M, 500 μL, 2mmol) was added and the unsealed mixture was stirred at room temperaturefor 1.5 hours. The mixture was concentrated under reduced pressure andthe residue was dissolved in DCM and concentrated under reducedpressure. This was repeated with DCM twice to chase off any excess HClto yield the title compound as a white powder (80 mg, over theory). m/z(ES+) 159 (M+H)⁺.

Compound 5.3. Methyl 3-iodo-4-methylbenzoate

To a solution of 3-iodo-4-methylbenzoic acid (28.0 g, 0.107 mol) in MeOH(300 mL) at 0° C. was carefully added concentrated H₂SO₄ (30 mL). Themixture was heated at 60° C. overnight, then cooled and the solventremoved under reduced pressure. The residue was carefully poured ontoice-water (200 mL) and the mixture was extracted with EtOAc (500 mL).The organics was washed with water (100 mL), saturated NaHCO₃ (100 mL),brine (100 mL), dried (MgSO₄), filtered, and concentrated to yield thetitle compound as a brown oil (29.0 g, 98%). ¹H NMR (400 MHz, CDCl₃) δ8.47 (d, J=1.7 Hz, 1H), 7.90 (dd, J=7.9 Hz, 1.7 Hz, 1H), 7.29 (d, J=7.9Hz, 1H), 3.90 (s, 2H), 2.48 (s, 3H).

Compound 5.4. Methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of methyl 3-iodo-4-methylbenzoate (compound 5.3, 5.00 g, 18.1mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.20g, 20.5 mmol), KOAc (5.33 g, 54.3 mmol) and PdCl₂(dppf).CH₂Cl₂ (0.74 g,0.91 mmol) in DMSO (50 mL) was degassed with argon. The mixture was thenheated at 80° C. under argon overnight. The mixture was allowed to coolthen partitioned between EtOAc (400 mL) and water (80 mL). The organicphase was washed with water (80 mL), saturated aqueous NaHCO₃ (80 mL),brine (80 mL), dried (MgSO₄), filtered, and concentrated under reducedpressure. The residue was purified with silica gel chromatography(hexanes:EtOAc 20:1) to yield the title compound as a white crystallinesolid (3.56 g, 71%). ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=1.9 Hz, 1H),7.97 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 3.90 (s, 3H),2.58 (s, 3H), 1.35 (s, 12H).

Compound 5.5. 5-Iodo-2,4-dimethyl-1H-imidazole

NIS (14.0 g, 62.4 mmol) was added portion-wise to a solution of2,4-dimethyl-1H-imidazole (5.00 g, 52.0 mmol) in acetonitrile (100 mL).The mixture was heated at 80° C. for 16 hours, then cooled to roomtemperature. The solvent was removed under reduced pressure and theresidue was partitioned between EtOAc (300 mL) and water (80 mL). Theorganic layer was washed with saturated sodium thiosulfate (50 mL),brine (50 mL), dried (MgSO₄) and concentrated under reduced pressure.The residue was purified with by silica gel column chromatography(hexanes:EtOAc 1:1 to 10% MeOH in EtOAc) to yield the title compound asa light yellow solid (8.56 g, 74%). m/z (ES+) 223 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 9.69 (br s, 1H), 2.38 (s, 3H), 2.19 (s, 3H).)

Compound 5.6. Methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate

Methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4, 3.56 g, 12.9 mmol), 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5, 3.43 g, 15.4 mmol), K₂CO₃ (5.33 g, 38.6 mmol) andPdCl₂(dppf).CH₂Cl₂ (1.05 g, 1.29 mmol) were added to a round bottomflask. The flask was purged with argon, then dioxane (70 mL) and water(20 mL) were added and the mixture was heated at 90° C. for 16 hours.The mixture was cooled then additional K₂CO₃ (1M, 25 mL, 25.0 mmol) andcatalyst PdCl₂(dppf).CH₂Cl₂ (1.0 g, 1.2 mmol) were added. The mixturewas heated at 90° C. for an additional 10 hours, then cooled to roomtemperature and filtered through Celite®. The solvent was removed underreduced pressure and the residue was cooled to 0° C. and acidified to pH3-4 with aqueous HCl (2 M). The acidic mixture was washed with EtOAc(150 mL) and then the aqueous material was adjusted to pH 10-11 withaqueous sodium hydroxide (2 M) and extracted with EtOAc (5×200 mL). Thecombined organic phases were dried (MgSO₄), filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (DCM to 5% MeOH in DCM) to yield the title compound as athick brown oil (2.42 g, 77%). m/z (ES+) 245 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.89-7.87 (m, 2H), 7.31 (d with fine str, J=8.6 Hz, 1H), 3.89(s, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H).

Compound 5.7. 3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acidhydrochloride

To a solution of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6, 0.66g, 2.7 mmol) in MeOH (5 mL) was added aqueous NaOH (2 M, 4.8 mL, 9.6mmol). The mixture was stirred at room temperature for 3 hours then theorganic solvent was removed under reduced pressure. The aqueous residuewas cooled to 0° C. and acidified to pH 3-4 with aqueous HCl (1 M). Themixture was concentrated to dryness and 5% methanol in DCM (20 mL) wasadded to the residue. The mixture was stirred at room temperature for 5minutes and the solids (inorganic salts) were filtered from solution.The filtrate was concentrated to yield the title compound as a brownfoam (0.484 g, 67%). m/z (ES+) 231 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ14.22 (br s, 1H), 14.16 (br s, 1H), 13.11 (br s, 1H), 7.97 (dd, J=8.0Hz, 1.8 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 2.58(s, 3H), 2.31 (s, 3H), 2.15 (s, 3H).

Compound 5.4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

To a mixture of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 5.7, 0.484 g, 2.10 mmol), 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2, 0.41 g, 2.10 mmol), HOBT (0.085 g, 7.40mmol) and EDCI (0.603 g, 3.15 mmol) in DMF (8 mL) was added DIEA (1.09mL, 6.3 mmol). The mixture was stirred at room temperature for 16 hours,then partitioned between EtOAc (300 mL) and water (30 mL). The organiclayer was washed with brine (3×30 mL) and the combined aqueous phaseswere back extracted with EtOAc (2×50 mL). All organic extracts werecombined, dried (MgSO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(EtOAc to 5% MeOH in EtOAc) to yield the title compound as a white solid(0.35 g, 45%). m/z (ES+) 371 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (dwith fine str., J=8.4 Hz, 2H), 7.54-7.48 (m, 2H), 7.44 (d with finestr., J=8.2 Hz, 2H), 7.30 (d, J=7.9 Hz, 1H), 4.77-4.56 (m, 2H),4.35-4.18 (m, 2H), 3.97-3.87 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.10(s, 3H).

Compound 6.1. Methyl 4-bromo-2-methylbenzoate

To a solution of 4-bromo-2-methylbenzoic acid (5.11 g, 23.8 mmol, 1.0equiv) in methanol (25 mL) was added dropwise ulfuric acid (2.0 mL) overabout 3 minutes (mildly exothermic). The resulting mixture was refluxedfor 4 hours. After cooling to room temperature, the reaction mixture wascarefully quenched into saturated aqueous NaHCO₃ (100 mL)(note—significant gas evolution) and extracted with dichloromethane (200mL×1 then 50 mL×1). The combined organic phases were washed with amixture of brine/saturated NaHCO₃ (9:1)(50 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to yield the title compound as acolorless oil (5.28 g, 97%). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J=8.0Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.38 (dd, J=1.6 Hz, 1H), 3.89 (s, 3H),2.58 (s, 3H).

Compound 6.2. Methyl 4-cyclobutyl-2-methylbenzoate

Cyclobutylzinc(II) bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added toa mixture of methyl 4-bromo-2-methylbenzoate (compound 6.1, 5.2 g, 22.7mmol) and PdCl₂(dppf).CH₂Cl₂ (1.85 g, 2.27 mmol). The mixture wasdegassed and the flask was filled with argon through a balloon. Themixture was heated at 65° C. under argon for 24 hours, then cooled to 0°C. and carefully quenched with water (10 mL). The mixture was dilutedwith EtOAc (200 mL) and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography (hexanes:EtOAc 30:1 to20:1) to yield the title compound as a clear oil (4.1 g, 89%). ¹H NMR(400 MHz, CDCl₃) δ 7.86 (d, 1H), 7.12-7.02 (m, 2H), 3.88 (s, 3H),3.59-3.48 (m, 1H), 2.59 (s, 3H), 2.35 (m, 2H), 2.22-1.96 (m, 3H),1.86-1.84 (m, 1H).

Compound 6.3. Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate

N-Iodosuccinimide (3.52 g, 15.6 mmol) was added portion-wise to asolution of methyl 4-cyclobutyl-2-methylbenzoate (compound 6.2, 3.2 g,15.6 mmol) in concentrated sulfuric acid (25 mL) at 0° C. The mixturewas stirred at 0° C. for 30 min and at RT for 2 hours, upon where themixture turned very thick. The mixture was again cooled to 0° C. andMeOH (30 mL) was slowly and carefully added. The mixture was heated at60° C. for 2 hours. After cooling to room temperature, the solvent wasremoved under reduced pressure and the residue was poured onto ice water(100 mL). The mixture was extracted with EtOAc (2×). The combinedorganic layers were washed with brine, then aqueous 1M NaHCO₃(note-significant gas evolution), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by silica gel columnchromatography (hexanes:EtOAc 30:1 to 20:1) to yield the title compoundas a light yellow oil (4.17 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s,1H), 7.14 (s, 1H), 3.87 (s, 3H), 3.67-3.54 (m, 1H), 2.57 (s, 3H),2.51-2.40 (m, 2H), 2.14-1.97 (m, 3H), 1.82-1.79 (m, 1H).

Compound 6.4. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate

A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 6.3,4.17 g, 12.6 mmol), Zn(CN)₂ (2.96 g, 25.2 mmol) and Pd(PPh₃)₄ (0.73 g,0.63 mmol) in DMF (30 mL) was degassed and the flask was charged withargon. The mixture was heated at 100° C. under argon overnight. Aftercooling to ambient temperature, the mixture was quenched with saturatedaq. FeSO₄ (20 mL) and diluted with EtOAc (200 mL). The greenish solidwas removed by filtration through Celite® and the filtrate waspartitioned between water and EtOAc. The organics was washed with brine,dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography(hexanes:EtOAc 30:1 to 20:1) to yield the title compound as a whitesolid (2.55 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.28 (s,1H), 3.90 (s, 3H), 3.86-3.82 (m, 1H), 2.68 (s, 3H), 2.55-2.45 (m, 2H),2.27-2.04 (m, 3H), 1.89-1.87 (m, 1H).

Compound 6.5. 5-Carbamoyl-4-cyclobutyl-2-methylbenzoic acid

To a 1-L round bottom flask was added methyl5-cyano-4-cyclobutyl-2-methylbenzoate (compound 6.4, 12.00 g, 52.3 mmol)and dissolved in DMSO (100 mL). With stirring, aqueous sodium hydroxide(1 M, 260 mL, 260 mmol) was added carefully and the mixture was purgedwith nitrogen. The mixture was stirred at 95° C. for 13 hours and thencooled to room temperature. The solution was washed with diethyl ether(100 mL) and the basic aqueous was acidified to pH˜2 by slow addition ofaqueous HCl (1M) followed by aqueous H₃PO₄ (1M). The precipitated solidswere filtered, and washed with water (2×100 mL), then dried to constantmass to yield the title compound as a white powder (11.68 g, 96%). m/z(ES−) 232 (M−H)⁻. ¹H NMR (400 MHz, DMSO-d₆): δ 12.75 (br s, 1H), 7.75(s, 1H), 7.74 (br s, 1H), 7.34 (br s, 1H), 7.28 (s, 1H), 3.90 (app p,J=9.0 Hz, 1H), 2.56 (s, 3H), 2.32-2.20 (m, 2H), 2.16-2.02 (m, 2H),2.00-1.87 (m, 1H), 1.82-1.71 (m, 1H).

Compound 6.5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-cyclobutyl-4-methylbenzamide

To a 4-mL vial was added 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2, 27 mg, −90% pure, 0.13 mmol), HOBt (20 wt % H₂O)(22 mg,0.13 mmol), EDC (27 mg, 0.14 mmol). A solution of5-carbamoyl-4-cyclobutyl-2-methylbenzoic acid (compound 6.5, 28 mg, 0.12mmol) in DMF (500 μL) was added followed by DIEA (83 μL, 0.48 mmol). Themixture was sealed and stirred at room temperature for 18 hours.Additional amine (3 mg, −0.015 mmol) and EDC (5 mg, −0.026 mmol) wereadded and the mixture was stirred at room temperature for an additional27 hours. The mixture was diluted with ethyl acetate (5 mL) and washedwith brine (8 mL). The aqueous was extracted with ethyl acetate (2 mL)and the combined organics was washed with brine, 1 M NaH₂PO₄, saturatedNaHCO₃ and brine (7 mL each). The product began precipitating out ofsolution after the final brine wash, so the organics was diluted withDCM (3 mL) and MeOH (˜200 μL). The organics was dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude product wastriturated with Et₂O (1.5 mL), filtered, and washed with Et₂O (0.5 mL)to yield the title compound as an off white powder (41.4 mg, 92%). m/z(ES+) 374 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.67 (d with fine str.,J=8.4 Hz, 2H), 7.40 (d with fine str., J=8.4 Hz, 2H), 7.32 (s, 1H), 7.25(s, 1H), 5.79 (br s, 1H), 5.70 (br s, 1H), 4.67-4.57 (m, 1H), 4.39-4.30(m, 1H), 4.28-4.18 (m, 1H), 4.00-3.86 (m, 3H), 2.46 (s, 3H), 2.42-2.31(m, 2H), 2.19-1.96 (m, 3H), 1.88-1.77 (m, 1H).

Compound 7.1. Methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl)benzoate

To a solution of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4, 600 mg, 2.17 mmol) in dioxane (20 mL) was added2-methyl-4-bromo imidazole (419 mg, 2.6 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (180mg, 0.22 mmol). The mixture was degassed argon and stirred for 10minutes then aqueous potassium carbonate (1M, 10 mL, 10 mmol) was addedand the mixture was stirred at 90° C. for 18 h. After cooling to ambienttemperature, the reaction mixture was diluted with EtOAc and filteredthrough Celite®. The organic phase was washed by brine, dried (MgSO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (0-5% MeOH in EtOAc) toyield the title compound as a foam (324 mg, 65%). m/z (ES+) 231 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.30 (br s, 1H), 7.86 (dd, J=7.9, 1.9 Hz, 1H),7.32 (d, J=7.9 Hz, 1H), 7.08 (s, 1H), 3.92 (s, 3H), 2.53 (s, 3H), 2.51(s, 3H).

Compound 7.2. Methyl3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoate

To a solution of methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl) benzoate(compound 7.1, 317 mg, 1.38 mmol) in carbon tetrachloride (30 mL) wasadded NCS (184 mg, 1.38 mmol). The mixture was stirred at 50° C. for 16hours, then cooled to room temperature and washed with brine, dried(MgSO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (0-50% EtOAc inhexanes) to yield the title compound as a solid (300 mg, 82%). m/z (ES+)265 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.55 (br s, 1H), 8.01-7.87 (m,2H), 7.37 (d, J=7.8 Hz, 1H), 3.91 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H).

Compound 7.3. 3-(5-Chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoicacid

A mixture of methyl3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoate (compound 7.2,10 mg, 0.038 mmol) in methanol (2 mL) and aqueous NaOH (2M, 0.2 mL, 0.4mmol) was stirred at 50° C. for 16 hrs. The organic solvent was removedunder reduced pressure and aqueous HCl (2 M) was added to the residueuntil a pH ˜3-4 was attained. The solvents were removed under reducedpressure to produce a white solid which was a mixture of the titlecompound and salts and used in the next step without furtherpurification. m/z (ES−) 249 (M−H)⁻.

Compound 7.4-(1-(3-(4-Chloro-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

A mixture of 3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoic acid(compound 7.3, ˜0.038 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2, 8.6 mg, 0.044 mmol), EDCI (12 mg, 0.063 mmol), HOBt (8mg, 0.044 mmol) and DIEA (28 μl, 0.16 mmol) in DMF (1 mL) was stirred atroom temperature for 16 hours. The reaction was diluted with water andextracted with EtOAc. The organic phase was washed with brine (howmuch), dried (MgSO₄), filtered, and concentrated under reduced pressure.The residue was purified by silica gel preparative TLC (8% MeOH in DCM)to yield the title compound as a foam (2.8 mg, 19% over 2 steps). m/z(ES+) 391 (M+H)⁺. ¹H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.69 (d,J=8.3 Hz, 2H), 7.54-7.40 (m, 3H), 7.37 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 4.80-4.58 (m, 2H), 4.41-4.19 (m, 2H), 4.03-3.92 (m, 1H), 2.49(s, 3H), 2.32 (s, 3H).

Compound 8.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)azetidin-3-yl)benzonitrile

To a 4-mL vial was added5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-cyclobutyl-4-methylbenzamide(compound 6, 39 mg, 0.104 mmol), dioxane (200 μL) and1,1-dimethoxy-N,N-dimethylethanamine (76 μL, 0.52 mmol). The mixture washeated at 90° C. for 3 hours then cooled to room temperature. Aceticacid (42 μL, 0.73 mmol) and hydrazine hydrate (30 μL, 0.62 mmol) wereadded and the mixture was stirred at 90° C. for 1 hour. The mixture wasdiluted with DCM (5 mL) and washed with aqueous NaH₂PO₄ (1M, 5 mL) thensaturated aqueous NaHCO₃ (5 mL). The organics was dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel preparative thin layer chromatography (DCM/8%MeOH) to yield the title compound as a white powder (18.7 mg, 43%). m/z(ES+) 412 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.65 (d with fine str.,J=8.4 Hz, 2H), 7.57 (s, 1H), 7.39 (d with fine str., J=8.4 Hz, 2H), 7.29(s, 1H), 4.61 (app t, J=9.6 Hz, 1H), 4.39 (app t, J=8.8 Hz, 1H),4.27-4.18 (m, 1H), 4.17-4.07 (m, 1H), 4.02-3.94 (m, 1H), 3.94-3.84 (m,1H), 2.50 (s, 3H), 2.48 (s, 3H), 2.25-2.11 (m, 2H), 2.11-1.88 (m, 3H),1.82-1.71 (m, 1H).

Compound 9.1. Methyl 4-cyclobutylbenzoate

To a stirred mixture of ZnBr₂ (83.0 g, 369 mmol) in THF (500 mL) undernitrogen at 0° C. was added a solution of bromo(cyclobutyl)magnesium(242 mL, 363 mmol, 1.5 M in THF) dropwise over 20 min. The resultingmixture was cooled to −40° C. and Pd(dppf)Cl₂ (2.00 g, 2.73 mmol) andmethyl 4-bromobenzoate (20.0 g, 93.0 mmol) were added. The resultingmixture was stirred at −40° C. for 1 h under nitrogen, and thencarefully quenched with saturated aqueous NH₄Cl (500 mL). The mixturewas extracted with ethyl acetate (3×500 mL) and the combined organiclayers were washed with brine (3×500 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield the title compound as alight yellow oil (18.0 g, crude).

Compound 9.2. Methyl 4-cyclobutyl-3-iodobenzoate

To a solution of methyl 4-cyclobutylbenzoate (compound 9.1, 2.00 g, 10.5mmol) in acetic acid (30 mL) was carefully added sodium periodate (1.00g, 4.68 mmol), iodine (3.00 g, 11.8 mmol) and sulfuric acid (0.15 g).The resulting mixture was stirred overnight at 100° C. After cooling toroom temperature, the reaction was then carefully quenched withsaturated aqueous Na₂S₂O₃ (30 mL) and the resulting mixture wasextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine (3×20 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to yield of the title compound as a yellow oil(1.50 g, 45%).

Compound 9.3. 4-Cyclobutyl-3-iodobenzoic acid

A solution of methyl 4-cyclobutyl-3-iodobenzoate (compound 9.2, 11.0 g,34.8 mmol) and sodium hydroxide (4.00 g, 100 mmol) in methanol (100 mL)and water (50 mL) was stirred at 50° C. overnight. After cooling toambient temperature, the volatile solvent was removed under reducedpressure. The residual aqueous material was washed with ethyl acetate(20 mL). The pH of the aqueous was then adjusted to 3-4 with aqueoushydrogen chloride (6 M). The resulting precipitate was collected byfiltration and dried to yield the title compound as a white solid (8.60g, 82%).

Compound 9.4-(1-(4-Cyclobutyl-3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 4-cyclobutyl-3-iodobenzoic acid (compound 9.3) was used in placeof 5-iodo-2,4-dimethylbenzoic acid (compound 1.3) and2-methoxyacetimidamide hydrochloride (compound 4.7) was used in place ofacetimidamide hydrochloride. m/z (ES+) 469 (M+H)⁺.

Compound 10.1. Methyl 4-cyclopropylbenzoate

Into a 1-L three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionmixture of ZnBr₂ (41.5 g, 184 mmol) and tetrahydrofuran (500 mL). Themixture was cooled to 0° C., then cyclopropylmagnesium bromide (2 M inTHF)(92 mL, 184 mmol) was added drop-wise with stirring over 30 min. Themixture was then cooled to −40° C. and Pd(dppf)Cl₂ (3.00 g, 4.1 mmol)was added portion-wise over 1 min. Methyl 4-bromobenzoate (10.0 g, 46.50mmol) in THF (50 mL) was added drop-wise over 30 min at −40° C. Theresulting mixture was allowed to warm to room temperature and stirredovernight. The reaction was then carefully quenched by the addition ofaqueous NH₄Cl (sat., 500 mL). The mixture was extracted with ethylacetate (3×300 mL) and the combined organic layers were washed withbrine (3×300 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography with petroleum ether as the eluent to yield 8.87 g(crude) of the title compound as a yellow oil.

Compound 10.2. Methyl 3-bromo-4-cyclopropylbenzoate

Into a 50-mL round-bottom flask, was placed a mixture of methyl4-cyclopropylbenzoate (compound 10.1, 500 mg, 2.84 mmol),N-bromosuccinimide (500 mg, 2.81 mmol) and trifluoroacetic acid (20 mL).The mixture was stirred overnight at 50° C., then cooled and carefullyquenched with water (10 mL). The mixture was extracted with ethylacetate (3×30 mL) and the combined organic layers were washed with brine(3×30 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith petroleum ether as the eluent to yield 0.5 g (69%) of the titlecompound as a yellow oil.

Compound 10.3. 3-Bromo-4-cyclopropylbenzoic acid

Into a 50-mL round-bottom flask, was placed a solution of methyl3-bromo-4-cyclopropylbenzoate (compound 10.2, 500 mg, 1.96 mmol) inmethanol (10 mL) and a solution of sodium hydroxide (500 mg, 12.5 mmol)in water (5 mL). The resulting solution was stirred overnight at 50° C.,then the volatiles were removed under reduced pressure. The pH of theresidual solution was adjusted to 6-7 with aqueous HCl (6 M). Theresulting solids were collected by filtration to yield 0.3 g (63%) ofthe title compound as a white solid.

Compound 10.4. 4-Cyclopropyl-3-formylbenzoic acid

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 3-bromo-4-cyclopropylbenzoic acid (compound 10.3, 500 mg, 2.07 mmol)in tetrahydrofuran/Et₂O (1:1, 20 mL). The solution was cooled to −78° C.then n-BuLi (2.5 M in THF) (1.8 mL, 4.5 mmol) was added drop-wise withstirring. The resulting solution was stirred for an additional 30 min at−78° C., then N,N-dimethylformamide (0.49 mL, 6.3 mmol) was addeddrop-wise over 10 min. The mixture was stirred for 2 h at −78° C., thenquenched with water (100 mL). The pH of the solution was adjusted to 3-4with aqueous HCl (6 M), then extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine (3×30 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1:5) as the eluent to yield 0.3 g (76%) of thetitle compound as a white solid.

Compound 10.5. 4-Cyclopropyl-3-(1-hydroxypropyl)benzoic acid

Into a 250-mL 3-necked round-bottom flask, purged and maintained with aninert atmosphere of nitrogen and containing THF (60 mL), was placed asolution of ethylmagnesium bromide (3 M in diethyl ether) (24.6 mL, 73.8mmol). A solution of 4-cyclopropyl-3-formylbenzoic acid (compound 10.4,3.5 g, 18.4 mmol) in THF (40 mL) was added drop-wise at room temperatureover 45 min. The resulting mixture was stirred for 1.5 h at roomtemperature, then carefully quenched with water/ice (50 mL). The mixturewas diluted with EtOAc (100 mL) and the organic layer was washed withaqueous NH₄Cl (sat., 2×100 mL) and the aqueous layers combined. The pHof the aqueous phase was adjusted to 3-4 with aqueous hydrogen chloride(2 M) and extracted with ethyl acetate (2×150 mL). The combined organicextracts were washed with brine (30 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with ethyl acetate:PE (1:10-2:1) as the eluentto yield 3.4 g (84%) of the title compound as a white solid.

Compound 10.6. 4-Cyclopropyl-3-propionylbenzoic acid

Into a 500-mL round-bottom flask, was placed a mixture of4-cyclopropyl-3-(1-hydroxypropyl)benzoic acid (compound 10.5, 3.4 g,15.44 mmol) in 1,2-dichloroethane (300 mL) and Dess-Martin periodinane(7.2 g, 16.9 mmol). The mixture was stirred for 1.5 h at roomtemperature and then the solids were removed with filtration. Thefiltrate was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography with ethyl acetate:PE (1:9)to methanol/ethyl acetate (20:1) as the eluent to yield 2.3 g (68%) ofthe title compound as a light yellow solid.

Compound 10.7. Methyl 4-cyclopropyl-3-propionylbenzoate

Into a 50-mL round-bottom flask, was placed a solution of4-cyclopropyl-3-propanoylbenzoic acid (compound 10.6, 500 mg, 2.29 mmol)in N,N-dimethylformamide (20 mL) and potassium carbonate (633 mg, 4.55mmol). The mixture was cooled to 0-5° C. then iodomethane (157 μL, 2.52mmol) was added drop-wise. The resulting mixture was stirred for 1 h at5-10° C., then quenched with water/ice (80 mL). The aqueous phase wasextracted with ethyl acetate (2×150 mL) and the combined organic layerswere washed with brine (20 mL), sodium carbonate (sat., 20 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Obtained400 mg (75%) of the title compound as a light brown oil.

Compound 10.4-(1-(4-Cyclopropyl-3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except methyl 4-cyclopropyl-3-propionylbenzoate (compound 10.7) was usedin place of methyl 2,4-dimethyl-5-propionylbenzoate (compound 1.5) and2-methoxyacetimidamide hydrochloride (compound 4.7) was used in place ofacetimidamide hydrochloride. m/z (ES+) 455 (M+H)⁺.

Compound 11.1. 4-Methyl-3-propionylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound10.6, except 3-bromo-4-methylbenzoic acid was used in place of3-bromo-4-cyclopropylbenzoic acid (compound 10.3).

Compound 11.4-(1-(3-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 4-methyl-3-propionylbenzoic acid (compound 11.1) was used inplace of 2,4-dimethyl-5-propionylbenzoic acid (compound 1.4) and2-methoxyacetimidamide hydrochloride (compound 4.7) was used in place ofacetimidamide hydrochloride. m/z (ES+) 429 (M+H)⁺.

Compound 12.4-(1-(3-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 3,except4-(1-(3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 11) was used in place of4-(1-(5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 2). m/z (ES+) 415 (M+H)⁺.

Compound 13.1. tert-Butyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

To a stirred solution of 1-bromo-4-iodobenzene (93.7 g, 331 mmol) intetrahydrofuran (800 mL) under nitrogen at −78° C. was added drop-wise asolution of butyllithium (150 mL, 2.43 M in THF) over 30 min. Theresulting solution was stirred for 2 h at −78° C. A solution oftert-butyl 4-oxopiperidine-1-carboxylate (60 g, 301 mmol) intetrahydrofuran (800 mL) was then added drop-wise with stirring at −78°C. over 30 min. The mixture was stirred for 1 h at −78° C., then thereaction was carefully quenched with water (350 mL). The resultingmixture was extracted with ethyl acetate (2×400 mL) and the combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:200-1:10) as theeluent to yield 91 g (85%) of the title compound as a yellow oil.

Compound 13.2. tert-Butyl4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate

A mixture of tert-butyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 13.1, 36g, 101 mmol), Pd(PPh₃)₄ (11.7 g, 10.1 mmol), and Zn(CN)₂ (17.9 g, 152.4mmol) in DMF (400 mL) under nitrogen was stirred overnight at 80° C. Themixture was cooled to ambient temperature, then the reaction wasquenched by the addition of 600 mL of FeSO₄ (aq., sat.) and diluted withethyl acetate. The resulting mixture was stirred vigorously thenfiltered through Celite® and washed with 1 M FeSO₄, water, and ethylacetate. The layers were separated and the aqueous phase was extractedwith ethyl acetate (2×300 mL). The combined organic layers were washedwith potassium carbonate (aq., sat., 200 mL), followed by brine (200mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:200-1:5) as the eluent to yield 23 g(75%) of the title compound as a white solid.

Compound 13.3. tert-Butyl4-(4-cyanophenyl)-4-fluoropiperidine-1-carboxylate

To a stirred solution of compound 13.2 (5.00 g, 16.5 mmol) indichloromethane (250 mL) at −78° C. under nitrogen was added drop-wiseDeoxo-Fluor® (4.4 g, 19.9 mmol). The resulting mixture was stirred for 1h at −78° C. The reaction mixture was then carefully quenched by theaddition of sodium bicarbonate (aq., sat., 50 mL) and extracted withdichloromethane (3×100 mL). The combined organic layers were washed withbrine (150 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:30) as the eluent to yield 2.5 g (35%) of the title compound as awhite solid.

Compound 13.4. 4-(4-Fluoropiperidin-4-yl)benzonitrile hydrochloride

The title compound was prepared using standard chemical manipulationsand a procedure similar to that used for the preparation of compound1.2, except using compound 13.3 in place of compound 1.1. m/z (ES+) 205(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.83 (d, J=6.3 Hz, 2H), 7.68 (d,J=6.3 Hz, 2H), 3.55-3.32 (m, 4H), 2.58-2.40 (m, 2H), 2.28-2.22 (m, 2H).

Compound 14.1. 4-Methyl-2-(trifluoromethyl)-1H-imidazole

Into a 250-mL round-bottom flask, purged and maintained with an inertatmosphere of nitrogen, was placed 2-oxopropanal (5 g, 27.8 mmol),acetic acid (150 mL), 1-ethoxy-2,2,2-trifluoroethanol (13.3 g, 83.2mmol), and ammonium acetate (17.1 g, 222 mmol). The mixture was stirredfor 18 h at 110° C., then cooled to room temperature and concentratedunder reduced pressure. The residue was quenched with water/ice (30 mL)and the aqueous phase was extracted with ethyl acetate (2×100 mL). Thecombined organic layers were washed with brine (30 mL) and concentratedunder reduced pressure. The residue was dissolved in aqueous hydrogenchloride (5 M, 20 mL) and washed with ethyl acetate (2×50 mL). The pH ofthe aqueous layer was adjusted to 8-9 with sodium carbonate, thenextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (30 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography with ethyl acetate:PE (1:5) as theeluent to yield 1.2 g (29%) of the title compound as a brown oil.

Compound 14.2. 4-Methyl-1H-imidazole-2-carbonitrile

Into a 250-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was placed4-methyl-2-(trifluoromethyl)-1H-imidazole (compound 14.1, 800 mg, 5.33mmol) and 5% aqueous ammonium hydroxide (50 mL). The resulting solutionwas stirred for 40 h at 25-30° C., then the pH of the solution wasadjusted to 5-6 with acetic acid. The aqueous phase was extracted withethyl acetate (3×150 mL) and the combined organic extracts were washedwith brine (2×50 mL) and aqueous Na₂CO₃ (sat., 2×20 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with ethyl acetate:PE(1:20-1:10) as the eluent to yield 350 mg (61%) of the title compound asa white solid.

Compound 14.3. 5-Iodo-4-methyl-1H-imidazole-2-carbonitrile

Into a 25-mL round bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was placed a mixture of4-methyl-1H-imidazole-2-carbonitrile (compound 14.2, 350 mg, 3.27 mmol)and aqueous sodium hydroxide (2 M, 5 mL) and stirred for 15 min at roomtemperature. This was followed by the drop-wise addition of a solutionof iodine (1.25 g, 4.92 mmol) in dichloromethane (5 mL). The resultingmixture was stirred for 24 h at room temperature, then diluted withwater/ice (10 mL). The aqueous layer was washed with DCM (10 mL), andthen the aqueous layer was acidified to pH 5-6 with acetic acid. Theaqueous phase was extracted with EtOAc (5×50 mL) and the combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated underreduced pressure to yield 500 mg (66%) of the title compound as a brownsolid.

Compound 14.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazole-2-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-Iodo-4-methyl-1H-imidazole-2-carbonitrile (compound 14.3) wasused in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z(ES+) 382 (M+H)⁺.

Compound 15.5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazole-2-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-Iodo-4-methyl-1H-imidazole-2-carbonitrile (compound 14.3) wasused in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used inplace of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z(ES+) 410 (M+H)⁺.

Compound 16.1. 3,3,3-Trifluoro-2-oxopropanal

Into a 100-mL round-bottom flask, was placed a mixture of3,3-dibromo-1,1,1-trifluoropropan-2-one (10.37 g, 38.43 mmol) and sodiumacetate (12.61 g, 153.7 mmol) in water (50 mL). The resulting solutionwas stirred overnight at 100° C., then cooled to room temperature andextracted with ethyl acetate (3×20 mL). The combined organic extractswere dried (Na₂SO₄), filtered, and concentrated under reduced pressureto yield 1.52 g (31%) of the title compound as light yellow oil.

Compound 16.2. 2-Methyl-4-(trifluoromethyl)-1H-imidazole

Into a 10-mL sealed tube, was placed a solution of acetaldehyde (296 μL,5.29 mmol), 3,3,3-trifluoro-2-oxopropanal (compound 16.1, 1.0 g, 7.9mmol), and 25% ammonium hydroxide (0.8 mL) in methanol (5 mL). Thesolution was stirred for 3 h at 0° C., then stirred at room temperatureovernight. The resulting mixture was concentrated under reduced pressureand then the residue was diluted with water (50 mL) The aqueous phasewas extracted with ethyl acetate (3×20 mL) and the combined organicextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The crude product was purified by chromatography to yield 430mg (54%) of the title compound as a light yellow solid.

Compound 16.3. 2-Methyl-1H-imidazole-4-carbonitrile

Into a 100-mL round-bottom flask, was placed a solution of2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2, 300 mg, 2.00mmol) in 5% ammonium hydroxide (35 mL). The resulting solution wasstirred for 4 days at room temperature, then the pH of the solution wasadjusted to 7 with acetic acid. The aqueous phase was extracted with ofethyl acetate (3×10 mL) and the combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to yield 170mg (79%) of the title compound as a light yellow solid.

Compound 16.4. 5-Iodo-2-methyl-1H-imidazole-4-carbonitrile

Into a 25-mL round-bottom flask, was placed a mixture of2-methyl-1H-imidazole-4-carbonitrile (compound 16.3, 50 mg, 0.47 mmol),N-iodosuccinimide (116 mg, 0.52 mmol) in ACN (5 mL). The resultingsolution was heated at reflux overnight, then cooled to room temperatureand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography with ethyl acetate/petroleum ether(1/2) to yield 60 mg (55%) of the title compound as a light yellowsolid.

Compound 16.5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-methyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-iodo-2-methyl-1H-imidazole-4-carbonitrile (compound 16.4) wasused in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used inplace of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z(ES+) 410 (M+H)⁺.

Compound 17.1. 3-Butyryl-4-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound10.6, except 3-bromo-4-methylbenzoic acid was used in place of3-bromo-4-cyclopropylbenzoic acid (compound 10.3) and propylmagnesiumbromide was used in place of ethylmagnesium bromide.

Compound 17.4-(1-(3-(4-ethyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 3-butyryl-4-methylbenzoic acid (compound 17.1) was used in placeof 2,4-dimethyl-5-propionylbenzoic acid (compound 1.4) and2-methoxyacetimidamide hydrochloride (compound 4.7) was used in place ofacetimidamide hydrochloride. m/z (ES+) 443 (M+H)⁺.

Compound 18.1. 2-Methyl-5-propionylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound10.6, except 5-bromo-2-methylbenzoic acid was used in place of3-bromo-4-cyclopropylbenzoic acid (compound 10.3).

Compound 18.4-(1-(5-(2,4-Dimethyl-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 2-methyl-5-propionylbenzoic acid (compound 18.1) was used inplace of 2,4-dimethyl-5-propionylbenzoic acid (compound 1.4). m/z (ES+)399 (M+H)⁺.

Compound 19.4-(1-(4-Ethyl-3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 4-ethylbenzoic acid was used in place of 2,4-dimethylbenzoic acidand 2-methoxyacetimidamide hydrochloride (compound 4.7) was used inplace of acetimidamide hydrochloride. m/z (ES+) 443 (M+H)⁺.

Compound 20.1. Methyl 4-(bromomethyl)-3-iodobenzoate

Into a 100-mL round-bottom flask, was placed a mixture of methyl3-iodo-4-methylbenzoate (compound 5.3, 3.00 g, 10.9 mmol) in CCl₄ (50mL), NBS (2.9 g, 16.3 mmol), azobisisobutyronitrile (360 mg, 2.19 mmol)and potassium carbonate (1.65 g, 11.9 mmol). The resulting mixture wasstirred overnight at 70° C., then cooled to room temperature andconcentrated under reduced pressure. The residue was diluted with EtOAc(100 mL) and the mixture was washed with brine (2×50 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1:20) as the eluent to yield 3.0 g (78%) of thetitle compound as a yellow solid.

Compound 20.2. Methyl 3-iodo-4-(methoxymethyl)benzoate

Into a 250-mL round-bottom flask, was placed a mixture of methyl4-(bromomethyl)-3-iodobenzoate (compound 20.1, 3.0 g, 8.5 mmol) andsodium methoxide (1.8 g, 33 mmol) in methanol (100 mL). The resultingsolution was stirred for 2 h at 50° C., then cooled to room temperatureand concentrated under reduced pressure. The residue was diluted withethyl acetate (50 mL) and the solids were filtered off. The filtrate wasconcentrated under reduced pressure to yield 2.0 g (77%) of the titlecompound as a yellow solid.

Compound 20.4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-(methoxymethyl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except methyl 3-iodo-4-(methoxymethyl)benzoate (compound 20.2) was usedin place of methyl-3-iodo-4-methylbenzoate (compound 5.3) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used inplace of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z(ES+) 429 (M+H)⁺.

Compound 21.1. 2,5-Diiodo-4-methyl-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.5, except 4-methyl-1H-imidazole (2.0 g, 24.4 mmol) was used in placeof 2,4-dimethyl-1H-imidazole and 2 equivalents of NIS was used to yield4.0 g (49%) of the title compound as a white solid.

Compound 21.2. 5-Iodo-4-methyl-1H-imidazole

Into a 250-mL round-bottom flask, was placed2,5-diiodo-4-methyl-1H-imidazole (compound 21.1, 1.0 g, 3.0 mmol),Na₂SO₃ (3.0 g, 25.4 mmol) and ethanol/water (20/40 mL). The resultingmixture was stirred overnight at reflux, then cooled and concentratedunder reduced pressure. The residue was dissolved in water (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere dried (Na₂SO₄), filtered, and concentrated under reduced pressureto yield 0.60 g (96%) of the title compound as a white solid.

Compound 21.4-(1-(4-methyl-3-(4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-iodo-4-methyl-1H-imidazole (compound 21.2) was used in place of5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used inplace of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z(ES+) 385 (M+H)⁺.

Compound 22.4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 3-iodobenzoic acid was used in place of5-iodo-2,4-dimethylbenzoic acid (compound 1.3). m/z (ES+) 385 (M+H)⁺.

Compound 23.1. Methyl 3-hydroxypropanimidate hydrochloride

Into a 50-mL 3-necked round-bottom flask, was placed a solution of3-hydroxypropanenitrile (2.00 g, 28.1 mmol) in ether (10 mL) andmethanol (5 mL). HCl gas was introduced by bubbling through thesolution. The resulting solution was stirred for 2 h at roomtemperature, then the resulting mixture was carefully concentrated underreduced pressure. The residue was washed with ether (2×20 mL) and thesolids were collected by filtration to yield 1.3 g (33%) of the titlecompound as a white solid.

Compound 23.2. 3-Hydroxypropanimidamide hydrochloride

Into a 50-mL 3-necked round-bottom flask, was placed a solution ofmethyl 3-hydroxypropanecarboximidate hydrochloride (compound 23.1, 2.00g, 14.3 mmol) in methanol (5 mL). The solution was cooled to 0° C. andammonia (gas) was introduced over 20 min. The resulting solution wasstirred for 2 h at room temperature, then concentrated under reducedpressure. The residue was washed with petroleum ether (2×20 mL) andEtOAc (2×20 mL) and the solids were collected by filtration to yield 1.6g (crude) of the title compound as a white solid.

Compound 23.4-(1-(3-(2-(2-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 4-methyl-3-propionylbenzoic acid (compound 11.1) was used inplace of 2,4-dimethyl-5-propionylbenzoic acid (compound 1.4) and3-hydroxypropanimidamide hydrochloride (compound 23.2) was used in placeof acetimidamide hydrochloride. m/z (ES+) 429 (M+H)⁺.

Compound 24.1.4-(1-(3-(2-(2-Chloroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

Into a 50-mL round-bottom flask, was placed a solution of4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 23, 75 mg, 0.18 mmol) in dichloromethane (5 mL). Thionylchloride (25 μL, 0.35 mmol) was added and the resulting solution wasstirred for 3 h at room temperature. The solvents were carefully removedunder reduced pressure to yield 50 mg (crude) of the title compound as ayellow solid.

Compound 24.4-(1-(3-(2-(2-(Dimethylamino)ethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

Into a vessel with condensor, was placed a solution of4-(1-(3-(2-(2-chloroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 24.1, 26 mg, 0.06 mmol, 1.00 equiv) in EtOH (10 mL).Dimethylamine (1 M in THF, 0.3 mL, 0.3 mmol) was added and the mixturewas sealed under a nitrogen balloon. The resulting solution was stirredovernight with a 100° C. oil bath. After cooling to room temperature,the resulting mixture was concentrated under reduced pressure and thecrude product was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; mobile phase, WATER WITH 0.03% NH₃H₂O and CH₃CN (31%CH₃CN up to 43% in 7 min, up to 100% in 0.5 min, down to 31% in 3.5min); Detector, Waters 2489, 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 6.3 mg (24%) of thetitle compound as a white solid. m/z (ES+) 456 (M+H)⁺.

Compound 25.1.4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 4-fluorobenzoic acid was used in place of 2,4-dimethylbenzoicacid.

Compound 25.4-(1-(4-(Azetidin-1-yl)-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

Into a 10-mL sealed tube, was placed a solution of4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile(compound 25.1, 200 mg, 0.50 mmol) in 1,4-dioxane (4 mL). Azetidinehydrochloride (50 mg, 0.53 mmol) and cesium carbonate (500 mg, 1.53mmol) were added and the mixture was stirred for 48 h at 120° C. behinda blast shield. The mixture was cooled and the solids were removed byfiltration. The filtrate was concentrated under reduced pressure and thecrude product was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, Water with 50 mmol NH₄HCO₃ and CH₃CN (33.0%CH₃CN up to 46.0% in 10 min, up to 100.0% in 3 min, down to 33.0% in 1min); Detector, Waters 2489, 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield 59.6 mg (27%) of thetitle compound as a white solid. m/z (ES+) 440 (M+H)⁺.

Compound 26.1. 4-Methyl-3-(2-methyl-1H-imidazol-4-yl)benzoic acid

Methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl) benzoate (compound 7.1,219 mg, 0.95 mmol) was dissolved in a mixture of methanol (20 mL) andaqueous sodium hydroxide (5 mL, 2M). The resulting solution was heatedat 50° C. for 16 hrs, then the reaction was cooled to room temperatureand the organic solvent was removed under reduced pressure. Theresulting aqueous residue was acidified to pH 3-4 with aqeuous HCl (2M). The resulting solids were collected and dried to yield 128 mg (62%)of the title compound as a white solid. m/z (ES−) 215 (M−H)⁻.

Compound 26.4-(1-(4-Methyl-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 4-methyl-3-(2-methyl-1H-imidazol-4-yl)benzoic acid (compound26.1, 65 mg, 0.30 mmol) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 74 mg,0.33 mmol) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). 79 mg (68%) of the title compound wasobtained as a white solid. m/z (ES+) 385 (M+H)⁺.

Compound 27.1. Methyl 3-acetyl-4-methylbenzoate

Into a 250-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was placed a mixture of methyl3-iodo-4-methylbenzoate (compound 5.3, 4.50 g, 16.3 mmol),1-(vinyloxy)butane (4.21 mL, 32.6 mmol), TEA (4.53 mL, 32.5 mmol),1,3-bis(diphenylphosphino)propane (672 mg, 1.63 mmol) and Pd(OAc)₂ (349mg, 1.55 mmol) in DMSO (50 mL). The mixture was stirred for 12 hours at120° C., then cooled to room temperature. The pH was adjusted to 1-2with aqueous hydrogen chloride (2 M) and stirred for 1 hour. The aqueousphase was extracted with ethyl acetate (3×200 mL) and the combinedorganic layers were washed with water (100 mL), then brine (3×100 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with ethylacetate/petroleum ether (1:50) as the eluent to yield 1.45 g (46%) ofthe title compound as a yellow solid.

Compound 27.2. Methyl 3-(2-bromoacetyl)-4-methylbenzoate

Into a 50-mL round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl3-acetyl-4-methylbenzoate (compound 27.1, 200 mg, 1.04 mmol) inchloroform (4 mL). Bromine (53 μL, 1.04 mmol) was added drop-wise andthe solution was stirred for 2 h at room temperature, then concentratedunder reduced pressure. Obtained 300 mg (crude) of the title compound asa brown solid.

Compound 27.3. Methyl3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate

Into a 50-mL round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl3-(2-bromoacetyl)-4-methylbenzoate (compound 27.2, 281 mg, 1.04 mmol) inACN (5 mL). 2-Methoxyacetimidamide (compound 4.7, 194 mg, 1.56 mmol) andpotassium carbonate (434 mg, 3.14 mmol) were added and the resultingmixture was stirred for 12 hours at 80° C., then concentrated underreduced pressure. The residue was diluted with water (50 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine (3×50 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography with ethyl acetate/petroleum ether (1:1) as the eluent toyield 50 mg (19%) of the title compound as a brown solid.

Compound 27.4. Methyl3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate

Into a 50-mL round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3,40 mg, 0.15 mmol) and NCS (24.6 mg, 0.18 mmol) in CCl₄ (20 mL). Theresulting mixture was stirred for 2 h at 50° C., then cooled to roomtemperature and quenched with water (100 mL). The aqueous phase wasextracted with ethyl acetate (100 mL) and the combined organic layerswere washed with brine (3×30 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield 30 mg (crude) of the titlecompound as a yellow solid.

Compound 27.5.3-(4-Chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid

Into a 50-mL round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was added methyl3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 27.4, 50 mg, 0.19 mmol) and sodium hydroxide (31 mg, 0.76mmol) in methanol/water (3 mL/3 mL). The resulting solution was stirredfor 12 hours at room temperature. The pH of the solution was adjusted to1-2 with hydrogen chloride (6 M), then concentrated under reducedpressure to yield 150 mg (crude) of the title compound as the HCl saltas white solid.

Compound 27.4-(1-(3-(4-Chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

Into a 50-mL round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was placed a solution of3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 27.5, 20 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL).4-Dimethylaminopyridine (17.4 mg, 0.14 mmol), EDC.HCl (27 mg, 0.14mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 15.5mg, 0.07 mmol, 1.00 equiv) were added and the resulting solution wasstirred for 12 h at room temperature. The reaction was quenched withwater (10 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with brine (10 mL), dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The residue was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water with 0.05% TFA and CH₃CN (35% CH₃CN up to 50% in 7 min, up to 100%in 3 min, down to 35% in 1 min); Detector, Waters 2489, 254 & 220 nm.The fractions containing pure compound were combined and lyophilized toyield 15 mg (47%) of the title compound as a white solid. m/z (ES+) 449(M+H)⁺.

Compound 28.1.3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid

Into a 50-mL round-bottom flask, was placed a solution of methyl3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 27.4, 380 mg, 1.29 mmol, 1.00 equiv) in HBr (40% in AcOH)(10mL). The solution was stirred overnight at 80° C., then cooled andconcentrated under reduced pressure. The crude residue was purified byprep-HPLC (WATER WITH 0.05% TFA and CH₃CN (0% CH₃CN in 3 min, then up to100% for 5 min, down to 0% in 1 min); Detector, 254 & 220 nm. Thefractions containing clean product were combined and lyophilized toyield 171 mg (50%) of the title compound as yellow crude oil.

Compound 28.4-(1-(3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 27,except 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 28.1) was used in place of3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 27.5) and 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2) was used in place of 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.2). m/z (ES+) 407 (M+H)⁺.

Compound 29.4-(1-(3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 27,except 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 28.1) was used in place of3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 27.5). m/z (ES+) 435 (M+H)⁺.

Compound 30.4-(1-(3-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 27,except 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 28.1) was used in place of3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 27.5) and 4-(3-Fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.2). m/z (ES+) 425 (M+H)⁺.

Compound 31.1. Methyl 5-iodo-2,4-dimethylbenzoate

A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 10.0 g,32.6 mmol, 90%) and sulfuric acid (10 mL) in methanol (100 mL) wasstirred overnight at 80° C. After cooling to room temperature, themixture was concentrated under reduced pressure and the residue wasdiluted with of ethyl acetate (200 mL). The resulting mixture was washedwith water (3×50 mL), sodium bicarbonate (aq. sat., 2×50 mL, caution:gas evolution), followed by brine (2×50 mL). The organic phase was driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure to yield 9.2 g (88%) of the title compound as a yellow oil.

Compound 31.4-(1-(5-(4-Chloro-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 27,except methyl 5-iodo-2,4-dimethylbenzoate (compound 31.1) was used inplace of methyl 3-iodo-4-methylbenzoate (compound 5.3), acetimidamidehydrochloride was used in place of 2-methoxyacetimidamide (compound 4.7)and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was usedin place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2).m/z (ES+) 405 (M+H)⁺.

Compound 32.4-(1-(5-(4-Chloro-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 27,except methyl 5-iodo-2,4-dimethylbenzoate (compound 31.1) was used inplace of methyl 3-iodo-4-methylbenzoate (compound 5.3) and acetimidamidehydrochloride was used in place of 2-methoxyacetimidamide (compound4.7). m/z (ES+) 433 (M+H)⁺.

Compound 33.4-(1-(3-(4-Chloro-2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 27,except methyl 3-iodobenzoate was used in place of methyl3-iodo-4-methylbenzoate (compound 5.3) and acetimidamide hydrochloridewas used in place of 2-methoxyacetimidamide (compound 4.7). m/z (ES+)405 (M+H)⁺.

Compound 34.4-(1-(3-(4-Chloro-2-methyl-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 27,except methyl 3-iodobenzoate was used in place of methyl3-iodo-4-methylbenzoate (compound 5.3), acetimidamide hydrochloride wasused in place of 2-methoxyacetimidamide (compound 4.7) and4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used inplace of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2).m/z (ES+) 377 (M+H)⁺.

Compound 35.(3-(4-chlorophenyl)pyrrolidin-1-yl)(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylphenyl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 3-(4-chlorophenyl)pyrrolidine was used in place4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+)394 (M+H)⁺.

Compound 36.1. tert-Butyl4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.1, except 6-bromo-[1,2,4]triazolo[4,3-a]pyridine was used in place of4-bromobenzonitrile. m/z (ES+) 303 (M+H)⁺.

Compound 36.2. 6-(Piperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine

To a solution of tert-Butyl4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate (compound36.1, 0.05 g, 0.165 mmol) in dichloromethane (2 mL) was added TFA (0.2mL). The mixture was stirred at room temperature for 3 hours. Thesolvents were removed under reduced pressure. The residue was purifiedby prep-TLC (10% MeOH in dichloromethane+˜0.5% NH₄OH) to give 0.25 g(76%) of the title compound as a light brown oil. m/z (ES+) 203 (M+H)⁺.

Compound 36.(4-([1,2,4]Triazolo[4,3-a]pyridin-6-yl)piperidin-1-yl)(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylphenyl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 6-(piperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (compound 36.2)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 415 (M+H)⁺. ¹H NMR (400 MHz, Methanol-d4) δ9.12 (d, J=0.8 Hz, 1H), 8.41 (d, J=1.4 Hz, 1H), 7.73 (dt, J=9.6, 1.0,1.0 Hz, 1H), 7.53 (dd, J=9.5, 1.6 Hz, 1H), 7.47-7.37 (m, 2H), 7.33 (d,J=1.7 Hz, 1H), 4.84 (m, 1H), 4.00 (m, 1H), 3.00 (m, 2H), 2.42 (s, 3H),2.32 (s, 3H), 2.14 (s, 3H), 2.10 (m, 1H), 1.96 (m, 1H), 1.77 (m, 3H).

Compound 37.4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) wasused in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound5.2). m/z (ES+) 399 (M+H)⁺. ¹H NMR (400 MHz, Methanol-d4) δ 7.65 (d,J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.34 (dd,J=7.20, 2.0 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H) 4.84-4.71 (m, 1H), 4.02-3.89(m, 1H), 3.03-2.91 (m, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 2.09 (s, 3H),2.00-1.64 (m, 5H).

Compound 38.(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylphenyl)(4-(imidazo[1,5-a]pyridin-7-yl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 7-(piperidin-4-yl)imidazo[1,5-a]pyridine hydrochloride (compound39.5) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 399 (M+H)⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.25 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.43-7.34 (m, 3H), 7.31-7.27 (m,2H), 6.68 (dd, J=7.6, 1.6 Hz, 1H), 4.85-4.76 (m, 1H), 4.04-3.93 (m, 1H),3.05-2.80 (m, 2H), 2.37 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H), 1.95-1.58(m, 5H).

Compound 39.1. (4-Bromopyridin-2-yl)methanamine

To a 1-L round-bottom flask, was placed a solution of4-bromopyridine-2-carbonitrile (10 g, 95%, 51.9 mmol; patent US2009/0239876 A1, example 2) in tetrahydrofuran (220 mL), then BH₃-THFcomplex (1 M) (330 mL) was added drop-wise with stirring at roomtemperature. The resulting solution was stirred overnight at roomtemperature, then carefully quenched with formic acid (100 mL). Themixture was concentrated under reduced pressure to yield the titlecompound as the formate salt which was a light yellow solid and was usedin the next step without further purification (8 g, crude).

Compound 39.2. N-((4-Bromopyridin-2-yl)methyl)formamide

To a 500-mL round-bottom flask, was placed(4-bromopyridin-2-yl)methanamine (compound 39.1, 8.0 g, crude) andformic acid (200 mL). The solution was stirred for 2 h at 100° C., thencooled and the pH was adjusted to 7 by careful and slow addition ofaqueous sodium carbonate (sat.). The aqueous phase was extracted withethyl acetate (3×200 mL) and the combined organic layers were washedwith brine (3×30 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography with ethyl acetate as the eluent to yield the titlecompound as a yellow oil (8.0 g, 90% pure, 65% yield over 2 steps).

Compound 39.3. 7-bromoimidazo[1,5-a]pyridine

To a 100-mL round-bottom flask, was placed a solution ofN-((4-bromopyridin-2-yl)methyl)formamide (compound 39.2, 3.0 g, 90%,12.6 mmol) in dichloromethane (20 mL). The solution was cooled to 0-5°C. then trifluoroacetic anhydride (1.93 mL, 13.9 mmol) was addeddrop-wise. The resulting solution was stirred for 1 h at roomtemperature, then the pH was adjusted to 7 by careful and slow additionof aqueous sodium carbonate (sat.). The aqueous phase was extracted withdichloromethane (3×20 mL) and the combined organic layers were washedwith brine (3×20 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography with ethyl acetate/petroleum ether (1/1) as the eluent toyield the title compound as a brown solid (1.0 g, 40%).

Compound 39.4. tert-Butyl4-(imidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.1, except 7-bromoimidazo[1,5-a]pyridine (compound 39.3) was used inplace of 4-bromobenzonitrile.

Compound 39.5. 7-(Piperidin-4-yl)imidazo[1,5-a]pyridine hydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.2, except tert-butyl4-(imidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 39.4)was used in place of tert-butyl4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1).

Compound 39.2-Cyclobutyl-5-(4-(imidazo[1,5-a]pyridin-7-yl)piperidine-1-carbonyl)-N,4-dimethylbenzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 7-(piperidin-4-yl)imidazo[1,5-a]pyridine hydrochloride (compound39.5) was used in place of 5-(piperidin-4-yl)-1H-indazole (compound62.5) to yield the title compound as a white solid. m/z (ES+) 431(M+H)⁺.

Compound 40.1.(E)-N′-((4-Bromopyridin-2-yl)methylene)-4-methylbenzenesulfonohydrazide

4-Bromopicolinaldehyde (2.0 g, 10.8 mmol) and4-methylbenzenesulfonohydrazide (2.0 g, 10.8 mmol) were mixed in MeOH(20 mL) and dichloromethane (20 mL). The mixture was stirred at roomtemperature for 1 hour. The solvents were removed under reduced pressureto give 3.80 g (theoretical) of the title compound as a yellow solid.m/z ES+354, 356 (M+H)⁺.

Compound 40.2. 5-Bromo-[1,2,3]triazolo[1,5-a]pyridine

A solution of(E)-N-((4-bromopyridin-2-yl)methylene)-4-methylbenzenesulfonohydrazide(compound 40.1, 3.8 g, 10.7 mmol) in morpholine (12 mL) was heated at130° C. for 3 hours. The reaction mixture was cooled to roomtemperature, then diluted with EtOAc (150 mL) and washed with water(2×30 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexanes:EtOAc 4:1) to yield 2.10 g (99%) ofthe title compound as a light yellow solid. m/z (ES+) 198, 200 (M+H)⁺.

Compound 40.3. tert-Butyl4-([1,2,3]triazolo[1,5-a]pyridin-5-yl)piperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.1, except tert-butyl4-([1,2,3]triazolo[1,5-a]pyridin-5-yl)piperidine-1-carboxylate (compound40.2) was used in place of 4-bromobenzonitrile. m/z (ES+) 303 (M+H)⁺.

Compound 40.4. 5-(Piperidin-4-yl)-[1,2,3]triazolo[1,5-a]pyridine

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound36.2, except tert-butyl4-([1,2,3]triazolo[1,5-a]pyridin-5-yl)piperidine-1-carboxylate (compound40.3) was used in place of tert-butyl4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate (compound36.1). m/z (ES+) 203 (M+H)⁺.

Compound 40.(4-([1,2,3]Triazolo[1,5-a]pyridin-5-yl)piperidin-1-yl)(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylphenyl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-(piperidin-4-yl)-[1,2,3]triazolo[1,5-a]pyridine (compound 40.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 415 (M+H)⁺. ¹H NMR (400 MHz, Methanol-d4) δ8.84 (d, J=7.2 Hz, 1H), 8.07 (d, J=0.8 Hz, 1H), 7.77 (t, J=0.8, 0.8 Hz,1H), 7.44-7.34 (m, 2H), 7.32 (d, J=1.6 Hz, 1H), 7.18 (dd, J=7.6, 2.0 Hz,1H), 4.87-4.76 (m, 1H), 4.08-3.92 (m, 1H), 3.11-2.95 (m, 2H), 2.37 (s,3H), 2.31 (s, 3H), 2.11 (s, 3H), 2.00-1.67 (m, 5H).

Compound 41.1. 4-Bromo-2-hydrazinylpyridine

To a solution of 4-bromo-2-fluoropyridine (2.0 g, 11.4 mmol) in pyridine(10 mL) was added hydrazine (5 mL, 159 mmol). The mixture was heated at70° C. for 2 hours, then cooled to room temperature. The volatileorganics were removed under reduced pressure, then water (60 mL) wasadded to the residue and an off-white solid precipitated. The solid wasfiltered, washed with water, and dried under reduced pressure at 50° C.to give 1.77 g (84%) of the title compound as an off-white solid. m/z(ES+) 188, 190 (M+H)⁺.

Compound 41.2. 7-Bromo-[1,2,4]triazolo[4,3-a]pyridine

4-Bromo-2-hydrazinylpyridine (compound 41.1) was suspended in formicacid (3 mL). The mixture was heated at 100° C. for one hour, then uponcomplete reaction, the mixture cooled to room temperature. The volatileorganics were removed under reduced pressure, then water (50 mL) wasadded to the residue. The solids that formed were filtered, washed withwater and dried under reduced pressure at 50° C. to give 1.68 g (90%) ofthe title compound as an off-white solid. m/z (ES+) 198, 200 (M+H)⁺.

Compound 41.3. tert-Butyl4-([1,2,4]triazolo[4,3-a]pyridin-7-yl)piperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.1, except 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (compound 41.2) wasused in place of 4-bromobenzonitrile. m/z (ES+) 303 (M+H)⁺.

Compound 41.4. 7-(Piperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound36.2, except tert-butyl4-([1,2,4]triazolo[4,3-a]pyridin-7-yl)piperidine-1-carboxylate (compound41.3) was used in place of tert-butyl4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate (compound36.1) m/z (ES+) 203 (M+H)⁺.

Compound 41.(4-([1,2,4]Triazolo[4,3-a]pyridin-7-yl)piperidin-1-yl)(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylphenyl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 7-(piperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (compound 41.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 415 (M+H)⁺. ¹H NMR (400 MHz, Methanol-d4) δ9.13 (s, 1H), 8.45 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.44-7.36 (m, 2H),7.33 (d, J=1.6 Hz, 1H), 7.07 (dd, J=7.2, 1.6 Hz, 1H), 4.87-4.78 (m, 1H),4.08-3.96 (m, 1H), 3.11-2.95 (m, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 2.13(s, 3H), 2.10-1.73 (m, 5H).

Compound 42.1. tert-Butyl4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate

Into a 1-L 3-necked round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution of1-chloro-4-iodobenzene (10.0 g, 41.9 mmol) in tetrahydrofuran (150 mL).The solution was cooled to −78° C., then n-BuLi (2.4 M) (16.6 mL, 39.8mmol) was added dropwise and the resulting mixture was stirred for 0.5 hat −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.60g, 38.1 mmol) in tetrahydrofuran (50 mL) was added dropwise and theresulting mixture was stirred for 1 h at −78° C. The reaction was thenwarmed to 0° C., and carefully quenched by the slow addition of water(150 mL). The layers were separated and the aqueous phase was extractedwith ethyl acetate (150 mL). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1:50 to 1:3) to yield the title compound as alight yellow solid (9.3 g, 78%).

Compound 42.2. tert-Butyl4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (compound 42.1,9.00 g, 28.9 mmol) in pyridine (50 mL). With stirring, phosphoroyltrichloride (7.93 mL, 84.8 mmol) was added drop-wise. The resultingmixture was stirred overnight at room temperature and then concentratedunder reduced pressure. The residue was diluted with ethyl acetate (20mL) and carefully quenched by slow addition of aqueous sodiumbicarbonate. The layers were separated and the organic layer was washedwith aqueous sodium bicarbonate (2×30 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with ethyl acetate/petroleum ether (1:100 to1:10) to yield the title compound as a colorless oil (6.1 g, 72%).

Compound 42.3. tert-Butyl 4-(4-chlorophenyl)piperidine-1-carboxylate

Into a 250-mL round-bottom flask, was placed a mixture of Pt₂O (200 mg)and methanol (50 mL). The mixture was purged with nitrogen, thenhydrogen was introduced and the mixture was stirred for 15 min. Asolution of tert-butyl4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 42.2,6.00 g, 20.4 mmol) in methanol (50 mL) was added and the resultingmixture was stirred under hydrogen overnight at room temperature. Afterpurging with nitrogen, the solids were filtered off and the resultingsolution was concentrated under vacuum to yield the title compound as alight green oil (5.30 g, 88%).

Compound 42.4. 4-(4-Chlorophenyl)piperidine

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl4-(4-chlorophenyl)piperidine-1-carboxylate (compound 42.3, 5.00 g, 16.9mmol) in dichloromethane (100 mL), trifluoroacetic acid (9.6 g, 84mmol). The resulting solution was stirred overnight at room temperatureand then concentrated under reduced pressure. The residue was carefullydiluted with ethyl acetate (100 mL) and aqueous sodium bicarbonate wasadded until a pH of 8 was attained. The resulting mixture was washedwith brine (100 mL) and the organic layer was dried (Na₂SO₄), filtered,and concentrated under reduced pressure to yield the title compound as alight yellow solid (2.30 g, 70%).

Compound 43.1. tert-Butyl3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate

Into a 1-L 3-necked round-bottom flask, purged and maintained with aninert atmosphere of nitrogen, was placed a solution of1-bromo-4-iodobenzene (25.0 g, 88.4 mmol) in tetrahydrofuran/diethylether (400/200 mL). The solution was cooled to −78° C. then n-BuLi (2.5M, 37.1 mL, 92.8 mmol) was added drop-wise over 10 min. To the resultingmixture was added tert-butyl 3-oxoazetidine-1-carboxylate (16.6 g, 97.0mmol) in THF (100 mL) drop-wise at −78° C. The resulting mixture wasstirred for 1.5 h at −78° C., then carefully quenched with water (300mL). The aqueous phase was extracted with ethyl acetate (200 mL) and thecombined organic layers were washed with brine (2×100 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1:20-1:5) as the eluent followed byre-crystallized from ethyl acetate:PE in the ratio of 1:100 to yield 8.0g (28%) of the title compound as a white solid.

Compound 43.2. tert-Butyl3-(4-cyanophenyl)-3-hydroxyazetidine-1-carboxylate

Into a 500-mL round-bottom flask, purged and maintained with an inertatmosphere of nitrogen, was placed a mixture of tert-butyl3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate (compound 43.1, 16.3g, 49.7 mmol) in N,N-dimethylformamide (250 mL), zinc cyanide (8.7 g, 75mmol) and Pd(PPh₃)₄ (5.77 g, 5.00 mmol). The resulting mixture wasstirred for 15 h at 100° C., then cooled to room temperature. Thereaction was quenched with saturated aqueous FeSO₄ (500 mL) and stirredvigorously. The mixture was filtered through Celite® and the layers fromthe filtrate were separated. The aqueous phase was extracted with ethylacetate (300 mL) and the combined organic layers were washed with brine(2×100 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith ethyl acetate/petroleum ether (1/100-1/3) as the eluent to yield 14g (crude) of the title compound as a white solid.

Compound 43.3. tert-Butyl3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate

Into a 250-mL 3-necked round-bottom flask, purged and maintained with aninert atmosphere of nitrogen, was placed a solution of tert-butyl3-(4-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (compound 43.2, 5.00g, 18.2 mmol) in dichloromethane (120 mL). The solution was cooled to−78° C. and Deoxo-Fluor® (bis(2-methoxyethyl)aminosulfur trifluoride)(5.99 g, 27.1 mmol) was added drop-wise. The resulting mixture wasstirred for 1.5 h at −78° C., then carefully quenched with sodiumbicarbonate (50 mL, 1 M). The organic layer was additionally washed withbrine (2×50 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography with ethyl acetate/petroleum ether (1/50-1/30) as theeluent to yield 3.2 g (64%) of the title compound as colorless oil.

Compound 43.4. 4-(3-Fluoroazetidin-3-yl)benzonitrile hydrochloride

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate (compound 43.3, 1.00g, 3.62 mmol) in dioxane (10 mL) and HCl in dioxane (4 M in dioxane, 10mL, 40 mmol). The resulting mixture was stirred for 1 h at 60° C., thencooled and concentrated under reduced pressure. The residue was washedwith EtOAc (20 mL) and the product solids were collected by filtrationto yield 522 mg (68%) of the title compound as a white solid. m/z (ES+)177 (M+H)⁺. ¹H NMR (300 MHz, CD3OD): δ 7.91 (d, J=7.8 Hz, 2H), 7.82 (d,J=8.1 Hz, 2H), 4.85-4.52 (m, 4H).

Compound 44.1. 2-Cyclopropyl-1H-imidazole

Into a 25-mL round-bottom flask, was placed a solution ofcyclopropanecarbaldehyde (500 mg, 7.13 mmol), oxaldehyde (455 mg, 7.84mmol) in methanol (5 mL). The solution was cooled to 0° C., then 25%ammonium hydroxide (1 mL) was added drop-wise. The resulting solutionwas stirred for 3 h at 0° C., then stirred at room temperatureovernight. The resulting mixture was concentrated under reduced pressureand the residue was dissolved in brine (50 mL). The aqueous phase wasextracted with ethyl acetate (3×10 mL) and the combined organic layerswere dried (Na₂SO₄), filtered, and concentrated under reduced pressureto yield 600 mg (78%) of the title compound as a light brown solid.

Compound 44.2. 2-Cyclopropyl-4,5-diiodo-1H-imidazole

Into a 100-mL round-bottom flask, was placed a solution of2-cyclopropyl-1H-imidazole (compound 44.1, 1.8 g, 16.6 mmol) in sodiumhydroxide (2 M, 40 mL). A solution of iodine (8.5 g, 33.5 mmol) indichloromethane (40 mL) was added drop-wise and the resulting mixturewas stirred overnight at room temperature. The aqueous layer wasseparated and neutralized with acetic acid and quenched by the additionof Na₂S₂O₃ (sat. aq.). The solids were collected by filtration to yield3.8 g (63%) of the title compound as a brown solid.

Compound 44.3. 2-Cyclopropyl-4-iodo-1H-imidazole

Into a 100-mL round-bottom flask, was placed a solution of sodiumsulfite (11.3 g, 89.7 mmol) in H₂O/EtOH (30/15 mL).2-Cyclopropyl-4,5-diiodo-1H-imidazole (compound 44.2, 3.8 g, 10.6 mmol)was added and the resulting solution was heated at reflux overnight. Thereaction was cooled and the volatiles were removed under reducedpressure. The solids were collected by filtration to yield 1.8 g (73%)of the title compound as a light brown solid.

Compound 45.1. 5-Iodo-2-isopropyl-1H-imidazole

The title compound was prepared using standard chemical manipulationsand a procedure similar to that used for the preparation of compound44.3, except 2-isopropyl-1H-imidazole was used in place of2-cyclopropyl-1H-imidazole (compound 44.1).

The compounds in TABLE 1 were prepared using standard chemicalmanipulations and procedures with readily available starting materialsor building blocks described in this manuscript. The utilized procedureswere similar to that used for the preparation of compound 7 using therespective imidazoles (2-methyl-4-bromo imidazole, compound 44.3, orcompound 45.1) and the respective amines (compound 1.2, compound 13.4,compound 42.4, compound 5.2, or compound 43.4).

TABLE 1 m/z (ES+) Cpd Name Structure (M + H)⁺ 46 4-(1-(3-(4-chloro-2-methyl-1H- imidazol-5-yl)-4- methylbenzoyl)piperidin-4- yl)benzonitrile

419 13 4-(1-(3-(4-chloro-2- methyl-1H- imidazol-5-yl)-4-methylbenzoyl)-4- fluoropiperidin-4- yl)benzonitrile

437 42 (3-(4-chloro-2- methyl-1H- imidazol-5-yl)-4- methylphenyl)(4-(4-chlorophenyl)piperidin- 1-yl)methanone

408 44 4-(1-(3-(4-chloro-2- cyclopropyl-1H- imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile

417 47 4-(1-(3-(4-chloro-2- cyclopropyl-1H- imidazol-5-yl)-4-methylbenzoyl)piperidin- 4-yl)benzonitrile

445 43 4-(1-(3-(4-chloro-2- cyclopropyl-1H- imidazol-5-yl)-4-methylbenzoyl)-3- fluoroazetidin-3- yl)benzonitrile

435 48 4-(1-(3-(4-chloro-2- cyclopropyl-1H- imidazol-5-yl)-4-methylbenzoyl)-4- fluoropiperidin-4- yl)benzonitrile

463 45 4-(1-(3-(4-chloro-2- isopropyl-1H- imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile

419 49 4-(1-(3-(4-chloro-2- isopropyl-1H- imidazol-5-yl)-4-methylbenzoyl)piperidin- 4-yl)benzonitrile

447

Compound 50.1. Methyl 4-chloro-3-iodo-benzoate

4-Chloro-3-iodo-benzoic acid (5.31 g, 18.8 mmol) was dissolved inmethanol (50 mL) and concentrated sulfuric acid (3 mL) was carefullyadded. The solution was stirred at 80° C. for 4 hours, then cooled toroom temperature and the volatile organics were removed under reducedpressure. The residue was partitioned between EtOAc (50 mL) and water(50 mL) and the organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography (SiO₂; 0-10% EtOAc in hexanes) to yield5.32 g (95%) of the title compound as an oil. ¹H NMR (400 MHz,Chloroform-d) δ 8.54 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.0 Hz, 1H),7.53 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).

Compound 50.2. Methyl4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of methyl 4-chloro-3-iodo-benzoate (compound 50.1, 3.85 g,13.0 mmol), bis(pinacolato)diboron (3.96 g, 15.6 mmol), Pd(dppf)Cl₂.DCM(531 mg, 0.65 mmol) and potassium acetate (3.83 g, 39.0 mmol) in DMSO(40 mL) was degassed with argon and then heated to 80° C. for 18 hours.The reaction mixture was cooled then diluted with ethyl acetate (200 mL)and sequentially washed with water, aqueous HCl (1 M), saturated aqueousNaHCO₃, and brine, then dried (MgSO₄), filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(SiO₂; 0-10% EtOAc in hexanes) to yield 1.92 g (49%) of the titlecompound as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.36 (d,J=2.3 Hz, 1H), 8.01 (dd, J=8.4, 2.3 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H),3.94 (s, 3H), 1.40 (s, 12H).

Compound 50.3. Methyl 4-chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoate

To methyl4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 50.2, 600 mg, 2.02 mmol) in dioxane (20 mL) was added5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5, 538 mg, 2.42 mmol) andPd(dppf)Cl₂.DCM (165 mg, 0.20 mmol). The mixture was degassed with argonand stirred for 10 minutes at room temperature, then an aqueouspotassium carbonate solution (1M, 10 mL) was added and the mixture wasstirred at 90° C. for 18 h. The mixture was cooled and diluted withEtOAc, then filtered through Celite®. The filtrate was washed withbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography (SiO₂; 0-100% EtOAc inhexanes) to yield 270 mg (50%) of the title compound as a foam. m/z(ES+) 265 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J=2.2 Hz,1H), 7.90 (dd, J=8.4, 2.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 3.91 (s, 3H),2.40 (s, 3H), 2.19 (s, 3H).

Compound 50.4. 4-Chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoic acid

Methyl 4-chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoate (compound50.3, 270 mg, 1.02 mmol) was dissolved in methanol (20 mL) and aqueousNaOH (2 M, 6 mL) then heated to 50° C. for 16 hrs. The volatile solventswere removed under reduced pressure and the resulting aqueous phase wasacidified to pH 5-6 with aqueous HCl (2M). The precipitated solids werefiltered, and dried to yield 230 mg (94%) of the title compound as awhite solid. m/z (ES−) 249 (M−H)⁻.

Compound 50.4-(1-(4-Chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was obtained as a white solid (77 mg, 54%) usingstandard chemical manipulations and procedures similar to those used forthe preparation of compound 5, except4-chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoic acid (compound 50.4,85 mg, 0.34 mmol) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was usedin place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2).m/z (ES+) 419 (M+H)⁺.

Compound 51.1. Methyl 4-methyl-3-(1H-pyrazol-5-yl)benzoate

To methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 mL) was added5-iodo-1H-pyrazole (674 mg, 3.5 mmol), and Pd(dppf)Cl₂.DCM (237 mg, 0.29mmol). The mixture was degassed with argon and stirred for 10 minutesthen an aqueous potassium carbonate solution (2 M, 8 mL) was added. Themixture was heated at 90° C. for 18 h, then cooled and diluted withEtOAc and filtered through Celite®. The filtrate was washed with brine,dried (MgSO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (SiO₂; 0-30% EtOAc inhexanes) to yield 258 mg (41%) of the title compound as a solid. m/z(ES+) 217 (M+H)⁺.

Compound 51.2. Methyl 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoate

Methyl 4-methyl-3-(1H-pyrazol-5-yl)benzoate (compound 51.1, 385 mg, 1.78mmol) was dissolved in 1,2-dichloroethane (60 mL), thenN-chlorosuccinimide (250 mg, 1.87 mmol) was added. The mixture wasstirred at room temperature for 16 hours then washed with brine, dried(MgSO₄), filtered, and concentrated under reduced pressure. The residuewas purified by flash chromatography (SiO₂; 0-20% EtOAc in hexanes) toyield 152 mg (34%) of the title compound as an oil. m/z (ES+) 251(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.07-7.94 (m, 2H), 7.63 (d,J=0.7 Hz, 1H), 7.47-7.34 (m, 1H), 3.93 (s, 3H), 2.36 (s, 3H).

Compound 51.3. 3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid

Methyl 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoate (compound 51.2, 133mg, 0.53 mmol) was dissolved in a mixture of aqueous NaOH (2 M, 3 mL)and methanol (10 mL). The solution was heated at 50° C. for 16 hrs thenthe volatiles were removed under reduced pressure. Aqueous HCl (2 M) wasadded to adjust the pH to 4-5 then concentrated to yield 150 mg of awhite solid which was used in the next step without furtherpurification. m/z (ES−) 235 (M−H)⁻.

Compound 51.4-(1-(3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was obtained as a white solid (69 mg, 34% over 2steps) using standard chemical manipulations and procedures similar tothose used for the preparation of compound 5, except3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3, ˜0.53mmol) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 377 (M+H)⁺.

Compound 52.4-(1-(3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 5,except 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3)was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 5.7) and 4-(4-fluoropiperidin-4-yl)benzonitrilehydrochloride (compound 13.4) was used in place of4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+)423 (M+H)⁺.

Compound 53.4-(1-(3-(4-Chloro-1H-pyrazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 5,except 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3)was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 5.7) and 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 405 (M+H)⁺.

Compound 54.4-(1-(3-(4-Chloro-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 51 andcompound 5, except 3-bromo-5-methyl-1H-pyrazole was used in place of5-iodo-1H-pyrazole. m/z (ES+) 391 (M+H)⁺. ¹H NMR (300 MHz, Methanol-d4):δ 7.77-7.69 (n, 3H), 7.64-7.59 (m, 3H), 7.46 (d, J=8.1 Hz, 1H), 4.84 (m,1H), 4.64 (m, 1H), 4.48 (m, 1H), 4.23 (m, 1H), 4.09 (m, 1H), 2.34 (s,3H), 2.33 (s, 3H).

Compound 55.4-(1-(3-(4-Chloro-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 51 andcompound 5, except 3-bromo-5-methyl-1H-pyrazole was used in place of5-iodo-1H-pyrazole and 4-(3-fluoroazetidin-3-yl)benzonitrilehydrochloride (compound 43.4) was used in place of4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+)409 (M+H)⁺.

The compounds in TABLE 2 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 51, 52, 53, 54 and 55.

TABLE 2 m/z (ES+) Cpd Name Structure (M + H)⁺  94 4-(1-(5-(4-chloro-1H-pyrazol-5-yl)-2,4- dimethylbenzoyl)-3- fluoroazetidin-3- yl)benzonitrile

409 136 4-(1-(5-(4-chloro-3- methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin- 3-yl)benzonitrile

405 140 4-(1-(3-(4-chloro-3- methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)piperidin- 4-yl)benzonitrile

419 141 4-(1-(3-(4-chloro-3- methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)-4- fluoropiperidin-4- yl)benzonitrile

437 142 4-(1-(5-(4-chloro-1H- pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin- 3-yl)benzonitrile

391

Compound 56.1. 5-Iodo-4-methyl-1H-pyrazole

To a solution of 4-methyl-1H-pyrazole (2.15 g, 26.1 mmol) dissolved inDMF (20 mL) was added N-iodosuccinimide (6.19 g, 26.1 mmol). The mixturewas stirred at RT for 16 hours and then diluted with water and filtered.The filtrate was extracted with EtOAc (2×50 mL), then the combinedorganic extracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography (SiO₂; 0-50% EtOAc in hexanes) to yield 2.19 g (41%) ofthe title compound as a white solid. m/z (ES+) 209 (M+H)⁺.

Compound 56.4-(1-(4-Methyl-3-(4-methyl-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 5,except 5-iodo-4-methyl-1H-pyrazole (compound 56.1) was used in place of5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) to yield the titlecompound as white solid. m/z (ES+) 357 (M+H)⁺.

Compound 57.4-(1-(4-Methyl-3-(4-methyl-1H-pyrazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 5,except 5-iodo-4-methyl-1H-pyrazole (compound 56.1) was used in place of5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used inplace of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z(ES+) 385 (M+H)⁺.

Compound 58.4-(3-Fluoro-1-(4-methyl-3-(4-methyl-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 5,except 5-iodo-4-methyl-1H-pyrazole (compound 56.1) was used in place of5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) wasused in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound5.2). m/z (ES+) 375 (M+H)⁺.

The compounds in TABLE 3 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 51, 56, 57 and 58.

TABLE 3 m/z (ES+) Cpd Name Structure (M + H)⁺ 145 4-(1-(4-methyl-3-(1H-pyrazol-5- yl)benzoyl)piperidin- 4-yl)benzonitrile

371 146 4-(1-(2,4-dimethyl- 5-(4-methyl-1H- pyrazol-5-yl)benzoyl)azetidin- 3-yl)benzonitrile

371 147 4-(1-(2,4-dimethyl- 5-(4-methyl-1H- pyrazol-5- yl)benzoyl)-3-fluoroazetidin-3- yl)benzonitrile

389 148 4-(1-(2,4-dimethyl- 5-(4-methyl-1H- pyrazol-5-yl)benzoyl)piperidin- 4-yl)benzonitrile

399

Compound 59.1. 5-Iodo-3,4-dimethyl-1H-pyrazole

NIS (5.62 g, 24.9 mmol) was added portion-wise to a solution of3,4-dimethyl-1H-pyrazole (2.0 g, 20.8 mmol) in CH₃CN (50 mL). Themixture was heated at 80° C. for 16 hours, upon where thick off-whitesolids formed. The mixture was cooled to room temperature and the solidwere filtered, washed with cold CH₃CN and dried under reduced pressureto yield 4.32 g (94%) of the title compound as an off-white solid. m/z(ES+) 223 (M+H)⁺.

Compound 59.2. Methyl 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except 5-iodo-3,4-dimethyl-1H-pyrazole (compound 59.1) was used inplace of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 245(M+H)⁺.

Compound 59.3. 3-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate(compound 59.2) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 231 (M+H)⁺.

Compound 59.4-(1-(3-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound59.3) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 371 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 12.43-12.17 (br, 1H),7.83 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.4 Hz, 2.0Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 4.71 (m, 1H),4.54-4.35 (m, 2H), 4.09-4.00 (m, 2H), 2.24 (s, 3H), 2.17 (s, 3H), 1.83(s, 3H).

Compound 60.4-(1-(3-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound59.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile (compound 43.4) wereused in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound5.2), respectively. m/z (ES+) 389 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ12.45-12.26 (br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H),7.65 (d, J=7.2 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H),4.98-4.42 (m, 4H), 2.25 (s, 3H), 2.17 (s, 3H), 1.83 (s, 3H).

Compound 61.4-(1-(4-Methyl-3-(5-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 5,except 4-bromo-5-methyl-1H-pyrazole was used in place of5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used inplace of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z(ES+) 385 (M+H)⁺.

Compound 62.1. 4-Cyclobutyl-5-iodo-2-methylbenzoic acid

To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound6.3, 35.0 g, 106 mmol) in methanol (200 mL) at 0-5° C. was added aqueoussodium hydroxide (12.7 g, 318 mmol in 100 mL water) drop-wise. Theresulting mixture was stirred for 3 h at 60° C., then cooled to ambienttemperature and the volatile organics were removed under reducedpressure. The pH of the remaining aqueous material was adjusted to ˜4with hydrogen chloride (aqueous, 2 M). The resulting solids werecollected by filtration and dried in an oven under reduced pressure toyield the title compound as a white solid (31.0 g, 93%).

Compound 62.2. 4-Cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid

Into a 50-mL high pressure autoclave reactor, was placed a solution of4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 62.1, 1.50 g, 4.74mmol) in methanol (20 mL). Pd(dppf)Cl₂ (320 mg, 0.44 mmol) andtriethylamine (1.27 mL, 9.09 mmol) were added and carbon monoxide (gas,40 atm) was introduced. (CAUTION: Highly toxic gas at high pressure. Allnecessary safety precautions were performed). The resulting mixture wasstirred overnight at 90° C., then cooled to room temperature. Thereaction was vented carefully using the necessary precautions, then theresulting mixture was concentrated under reduced pressure. The residuewas dissolved in water (20 mL) and the pH of the solution was adjustedto 3-4 with aqueous HCl (1 M) and the resulting mixture was extractedwith ethyl acetate (3×20 mL). The combined organic extracts were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1/2-1/1) as the eluent to yield the titlecompound as a white solid (1.0 g, 85%).

Compound 62.3. 4-Cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid

Into a 20-mL sealed tube, was placed4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 62.2,1.0 g, 4.0 mmol) and methylamine (30% in ethanol) (8 mL). The resultingsolution was stirred overnight at 120° C. behind a blast shield, thencooled and diluted with H₂O (20 mL). The pH of the solution was adjustedto 4-5 with hydrogen chloride (1 M) and the solids were collected byfiltration. The crude product was re-crystallized from ethylacetate/petroleum ether in the ratio of 1:10 to yield the title compoundas an off-white solid (500 mg, 50%).

Compound 62.4. tert-Butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate

Into a 50-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a suspensionof Zn (990 mg, 15.1 mmol) in DMA (1 mL). A 7:5 v/v mixture ofTMSCl/1,2-dibromoethane (0.12 mL) was added drop-wise at a rate tomaintain the temperature below 65° C., then the mixture was stirred foran additional 10 min. A solution of tert-butyl4-iodopiperidine-1-carboxylate (3.17 g, 10.2 mmol) in DMA (2 mL) wasadded drop-wise and stirred at 40-45° C. for 30 min. The resultingmixture was added to a mixture of 5-bromo-1H-indazole (1.00 g, 5.08mmol), CuI (80 mg, 0.42 mmol) and Pd(dppf)Cl₂ (260 mg, 0.36 mmol) in DMA(1 mL) in a 50-mL round-bottom flask under a nitrogen atmosphere. Theresulting mixture was stirred overnight at 85° C., then cooled anddiluted with ethyl acetate (50 mL) and washed with brine (3×20 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with ethylacetate/petroleum ether (1/5) as the eluent to yield the title compoundas a yellow solid (200 mg, 12%).

Compound 62.5. 5-(Piperidin-4-yl)-1H-indazole

Into a 50-mL round-bottom flask, was placed a solution of tert-butyl4-(1H-indazol-5-yl)piperidine-1-carboxylate (compound 62.4, 200 mg, 0.60mmol) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). Theresulting solution was stirred for 1 h at room temperature, then the pHof the solution was carefully adjusted to 8-9 with aqueous sodiumbicarbonate (aq. sat.). The mixture was extracted with dichloromethane(3×30 mL) and the combined organic layers were dried (Na₂SO₄), filtered,and concentrated under reduced pressure to yield the title compounds asa yellow oil (100 mg, 75%).

Compound 62.5-(4-(1H-Indazol-5-yl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide

Into a 50-mL round-bottom flask, was placed a solution of5-(piperidin-4-yl)-1H-indazole (compound 62.5, 100 mg, 0.50 mmol) inN,N-dimethylformamide (3 mL). EDC.HCl (192 mg, 1.00 mmol),4-dimethylaminopyridine (122 mg, 1.00 mmol) and4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3,122 mg, 0.49 mmol) were added and the resulting solution was stirred for4 h at room temperature. The reaction was diluted with water (20 mL) andextracted with of ethyl acetate (2×25 mL). The combined organic layerswere washed with brine (2×15 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with ethyl acetate as the eluent, followed byadditional purification by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 0.05% TFA and CH₃CN (30% CH₃CN up to47% in 7 min, up to 100% in 3 min, down to 30% in 1 min); Detector,Waters 2489, 254 & 220 nm. The fractions containing pure compound werecombined and lyophilized to yield the title compound as a white solid(71.2 mg, 33%). m/z (ES+) 431 (M+H)⁺.

Compound 63.1. 1-Bromo-3-(2,2-diethoxyethoxy)benzene

Into a 3-L three neck round-bottom flask, was placed a solution of3-bromophenol (50.00 g, 289.0 mmol) in N,N-dimethylformamide (1 L). Thesystem was purged with nitrogen and the solution was cooled to 0° C.,then sodium hydride (60%, 12.8 g, 320 mmol) was added portion-wise. Tothe resulting mixture was added 2-bromo-1,1-diethoxyethane (53.1 mL, 345mmol) drop-wise at 0° C. The resulting mixture was stirred overnight at120° C., behind a blast shield (CAUTION: NaH and DMF can become arunaway reaction. All necessary safety precautions were performed). Themixture was cooled to room temperature, then diluted with ethyl acetate(3 L). The mixture was washed with brine (4×500 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with ethylacetate/petroleum ether (1/50-1/30) as the eluent to yield the titlecompound as a light yellow oil (78.9 g, 94%).

Compound 63.2 and compound 63.3. 6-Bromo-3a,7a-dihydrobenzofuran and4-bromo-3a,7a-dihydrobenzofuran

Into a 1-L round-bottom flask, was carefully placed a mixture of1-bromo-3-(2,2-diethoxyethoxy)benzene (compound 63.1, 62.9 g, 218 mmol)and polyphosphoric acid (157 g) in chlorobenzene (320 mL). The mixturewas stirred overnight at 90° C., then the mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wascarefully and slowly diluted with water (200 mL) and extracted withEtOAc (3×200 mL). The organic extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with ethyl acetate/petroleum ether (1:50-1:30)as the eluent to yield a mixture of the title compounds as a brown oil(20 g, crude).

Compound 63.4 and compound 63.5. tert-Butyl4-(benzofuran-6-yl)piperidine-1-carboxylate and tert-butyl4-(benzofuran-4-yl)piperidine-1-carboxylate

Into a 50-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a suspensionof Zn (1.13 g, 17.3 mmol) in DMA (5 mL). A 7:5 v/v mixture ofTMSCl/1,2-dibromoethane (0.5 mL) was added to the reaction flaskdrop-wise to maintain the temperature below 65° C., then the mixture wasstirred for an additional 10 min. To this mixture was added a solutionof tert-butyl 4-iodopiperidine-1-carboxylate (5.40 g, 17.4 mmol) in DMA(40 mL) drop-wise with stirring and the resulting mixture was stirred atroom temperature for 1 hour. The above mixture was filtered, and addedto a mixture of 6-bromo-3a,7a-dihydrobenzofuran (compound 63.2) and4-bromo-3a,7a-dihydrobenzofuran (compound 63.3) (2.83 g, 14.2 mmol), andCuI (274 mg, 1.44 mmol), Pd(dppf)Cl₂ (1.18 g, 1.6 mmol) in DMA (30 mL).The resulting mixture was stirred overnight at 85° C., then cooled toroom temperature. The solids were removed by filtration and the filtratewas diluted with ethyl acetate (200 mL) and washed with brine (3×80 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with ethylacetate/petroleum ether (1/30-1/20) as the eluent to yield tert-butyl4-(1-benzofuran-6-yl)piperidine-1-carboxylate (compound 63.4) as acolorless oil (267 mg, 6%) and tert-butyl4-(1-benzofuran-4-yl)piperidine-1-carboxylate (compound 63.5) as anoff-white solid (320 mg, 7%).

Compound 63.6. 4-(Benzofuran-6-yl)piperidine

Into a 50-mL round-bottom flask, was placed a solution of tert-butyl4-(1-benzofuran-6-yl)piperidine-1-carboxylate (compound 63.4, 200 mg,0.66 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL).The resulting solution was stirred at 15° C. for 1 hour, then the pH wascarefully adjusted to ˜9 with aqueous sodium hydroxide (2 M). Themixture was diluted with H₂O (20 mL) and the layers were separated. Theaqueous phase was extracted with dichloromethane (4×20 mL) and thecombined organic layers were washed with brine (30 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure to yield the titlecompound as a brown oil (150 mg, crude).

Compound 63.5-(4-(Benzofuran-6-yl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide

Into a 25-mL round-bottom flask, was placed a solution of4-(benzofuran-6-yl)piperidine (compound 63.6) (110 mg, 0.55 mmol),4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3,135 mg, 0.55 mmol), EDC.HCl (210 mg, 1.10 mmol) and4-dimethylaminopyridine (133.5 mg, 1.09 mmol) in N,N-dimethylformamide(3 mL). The resulting solution was stirred for 2 h at 15° C. thendiluted EtOAc (60 mL). The resulting mixture was washed with aqueoussaturated NH₄Cl (2×20 mL) and brine (20 mL), dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The crude product (110 mg) waspurified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 0.05% TFA and CH₃CN (51.0% CH₃CN upto 60.0% in 9 min, up to 100.0% in 5 min, down to 51.0% in 1 min);Detector, Waters 2489, 254 & 220 nm. The fractions containing purecompound were combined and lyophilized to yield the title compound as awhite solid (46.0 mg, 20%). m/z (ES+) 431 (M+H)⁺.

Compound 64.1. (Aminooxy)diphenylphosphine oxide

Into a 500-mL three neck round-bottom flask, was placed a solution ofhydroxylamine hydrochloride (30.0 g, 432 mmol) in H₂O/dioxane (90/45mL). The solution was cooled to 0-5° C., then sodium bicarbonate (36.5g, 434 mmol) was added portion-wise over 10 min and the mixture wasstirred at 0-5° C. for 30 min. A solution of diphenylphosphinoylchloride (41.0 g, 173 mmol) in dioxane (45 mL) was added drop-wise at0-5° C. over 30 min, then the resulting mixture was stirred for anadditional 2 h at ambient temperature. The resulting solids werecollected by filtration and washed with water (200 mL), NaOH (0.25 M,200 mL) and PE (200 mL). The product was dried to yield the titlecompound as a white solid (20 g, crude).

Compound 64.2. 1-Amino-4-bromopyridin-1-ium iodide

Into a 250-mL round-bottom flask, was placed a solution of4-bromopyridine hydrochloride (13.8 g, 71.0 mmol) in water (50 mL). Thesolution was cooled to 0-5° C. then sodium bicarbonate (12.0 g, 141mmol) was added portion-wise over 10 min and the mixture was stirred at0-5° C. for 30 min. The mixture was extracted with DCM (4×50 mL) and thecombined organic layers were washed with brine (50 mL), dried (Na₂SO₄),and filtered. The filtrate was placed into a 500-mL round-bottom flask,then purged and maintained with an inert atmosphere of nitrogen.(Aminooxy)diphenylphosphine oxide (compound 64.1, 20 g, ˜70% purity, 60mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction was carefully quenched with aqueous HI (8 mL,45%) and stirred for 30 min. The solids were collected by filtration,and washed with DCM (200 mL) and hexanes (200 mL) to yield the titlecompound as a brown solid (15 g, crude).

Compound 64.3. Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate

Into a 250-mL three neck round-bottom flask, was placed a solution of1-amino-4-bromopyridin-1-ium iodide (compound 64.2, 15 g, ˜50% purity,24.9 mmol) in N,N-dimethylformamide (80 mL). Potassium carbonate (10.6g, 76.7 mmol) was added portion-wise followed by the addition of ethylpropiolate (11.7 mL, 115 mmol) drop-wise over 10 min. The resultingmixture was stirred overnight at room temperature, then diluted withEtOAc (300 mL) and water (100 mL). The solids were removed by filtrationand the organic layer was washed with brine (3×50 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with ethylacetate/petroleum ether (1:10) as the eluent to yield the title compoundas a brown solid (300 mg, 6%).

Compound 64.4. 5-Bromopyrazolo[1,5-a]pyridine

Into a 50-mL round-bottom flask, was placed ethyl5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (compound 64.3, 100 mg,0.37 mmol). Sulfuric acid (50%, 4 mL) was added carefully in portions atroom temperature, then the resulting solution was stirred overnight at80° C. After cooling to room temperature, the pH of the solution wascarefully adjusted to 8-9 with aqueous sodium hydroxide (5 M) and thenextracted with ethyl acetate (2×20 mL). The combined organic extractswere washed with brine (20 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with ethyl acetate/petroleum ether (1:10) asthe eluent to yield the title compound as a brown solid (40 mg, 55%).

Compound 64.2-Cyclobutyl-N,4-dimethyl-5-(4-(pyrazolo[1,5-a]pyridin-5-yl)piperidine-1-carbonyl)benzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 5-bromopyrazolo[1,5-a]pyridine (compound 64.4) was used in placeof 5-bromo-1H-indazole to yield the title compound as a white solid. m/z(ES+) 431 (M+H)⁺.

Compound 65.(4-Cyclobutyl-3-(2,4-dimethyl-1H-imidazol-5-yl)phenyl)(4-(imidazo[1,5-a]pyridin-7-yl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except 4-cyclobutyl-3-iodobenzoic acid (compound 9.3) was used in placeof 5-iodo-2,4-dimethylbenzoic acid (compound 1.3) and7-(piperidin-4-yl)imidazo[1,5-a]pyridine hydrochloride (compound 39.5)was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2) to yield the title compound. m/z (ES+) 454 (M+H)⁺.

Compound 66.1. 1-(4-Bromopyridin-2-yl)ethanamine

Into a 500-mL 3-necked round-bottom flask, purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methylmagnesiumbromide (3 M in THF) (63.4 mL, 190 mmol) in THF (100 mL). A solution of4-bromopyridine-2-carbonitrile (11.6 g, 63.4 mmol; patent US2009/0239876 A1, example 2) in THF (40 mL) was added drop-wise at roomtemperature over 40 min. Methanol (40 mL) was then added drop-wisefollowed by portion-wise addition of sodium borohydride (11.8 g, 312mmol) in several batches. The resulting mixture was stirred at roomtemperature for 2 h, then diluted with ethyl acetate (200 mL). The pH ofthe mixture was adjusted to 9 with aqueous sodium hydroxide (1 M) andthe solids were removed by filtration. The filtrate was extracted withethyl acetate (2×100 mL) and the combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to yield 10.3 g (crude) of the title compound as a yellow oil.

Compound 66.2. 1-Methyl-7-(piperidin-4-yl)imidazo[1,5-a]pyridinehydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound39.5, except 1-(4-bromopyridin-2-yl)ethanamine (compound 66.1) was usedin place of (4-bromopyridin-2-yl)methanamine (compound 39.1).

Compound 67.1. N-((4-Bromopyridin-2-yl)methyl)acetamide

Into a 500-mL round-bottom flask, purged and maintained with an inertatmosphere of nitrogen, was placed a solution of(4-bromopyridin-2-yl)methanamine (compound 39.1, 4.5 g, 24.1 mmol) indichloromethane (160 mL). Triethylamine (6.72 mL, 48.2 mmol) and aceticanhydride (2.29 mL, 24.2 mmol) were carefully added and the resultingsolution was stirred at room temperature for 12 h. The volatiles wereremoved under reduced pressure and the residue was slowly quenched withwater (200 mL). The pH of the solution was slowly adjusted to 9-12 withaqueous sodium carbonate (3 M) and the aqueous phase was extracted withethyl acetate (3×60 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith dichloromethane/methanol (100:1-10:1) as the eluent to yield 4.0 g(73%) of the title compound as yellow oil.

Compound 67.2. 3-Methyl-7-(piperidin-4-yl)imidazo[1,5-a]pyridinehydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound39.5, except N-((4-bromopyridin-2-yl)methyl)acetamide (compound 67.1)was used in place of N-((4-bromopyridin-2-yl)methyl)formamide (compound39.2).

Compound 68.1 and compound 68.2. tert-Butyl4-(1-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate andtert-butyl4-(3-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate

Into a 25-mL round-bottom flask, was placed a solution of tert-butyl4-(imidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 39.4,170 mg, 0.56 mmol) in CCl₄ (3 mL). N-Chlorosuccinimide (75 mg, 0.56mmol) was added and the resulting mixture was stirred for 5 h at roomtemperature. The mixture was diluted with EtOAc (30 mL) and washed withbrine (3×20 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by preparative TLC with ethylacetate/petroleum ether (1/1) to yield 45 mg (24%) of tert-butyl4-(1-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound68.1) as a yellow solid and 64 mg (34%) of tert-butyl4-(3-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound68.2) as a yellow solid.

Compound 68.3. 1-Chloro-7-(piperidin-4-yl)imidazo[1,5-a]pyridinehydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.2, except tert-butyl4-(1-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound68.1) was used in place of tert-butyl4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1) to yield thetitle compound as a yellow solid.

Compound 71.1. 3-Chloro-7-(piperidin-4-yl)imidazo[1,5-a]pyridinehydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.2, except tert-butyl4-(3-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound68.2) was used in place of tert-butyl4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1) to yield thetitle compound as a yellow solid.

The compounds in TABLE 4 were prepared using standard chemicalmanipulations and procedures with readily available starting materialsor building blocks described in this manuscript. The utilized procedureswere similar to that used for the preparation of compound 1, using5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound1.8) and the respective amines (compound 5.2, compound 39.5, compound66.2, compound 67.2, compound 68.3, or compound 71.1).

TABLE 4 m/z (ES+) Cpd Name Structure (M + H)⁺ 69 4-(1-(5-(2,4-dimethyl-1H- imidazol-5-yl)-2,4- dimethylbenzoyl)azetidin-3-yl)benzonitrile

385 70 (5-(2,4-dimethyl- 1H-imidazol-5-yl)-2,4- dimethylphenyl)(4-(imidazo[1,5-a]pyridin- 7-yl)piperidin-1- yl)methanone

428 66 (5-(2,4-dimethyl- 1H-imidazol-5-yl)- 2,4-dimethylphenyl)(4-(1-methylimidazo[1,5- a]pyridin-7-yl)piperidin- 1-yl)methanone

442 67 (5-(2,4-dimethyl- 1H-imidazol-5-yl)- 2,4-dimethylphenyl)(4-(3-methylimidazo[1,5 a]pyridin-7-yl)piperidin- 1-yl)methanone

442 68 (4-(1- chloroimidazo[1,5- a]pyridin-7- yl)piperidin-1-yl)(5-(2,4-dimethyl- 1H-imidazol-5-yl)-2,4- dimethylphenyl)methanone

462 71 (4-(3- chloroimidazo[1,5- a]pyridin-7-yl)piperidin-1-yl)(5-(2,4-dimethyl- 1H-imidazol-5-yl)-2,4- dimethylphenyl)methanone

462

Compound 72.(4-Cyclopropyl-3-(2,4-dimethyl-1H-imidazol-5-yl)phenyl)(4-(1-methylimidazo[1,5-a]pyridin-7-yl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except methyl 4-cyclopropyl-3-propionylbenzoate (compound 10.7) was usedin place of methyl 2,4-dimethyl-5-propionylbenzoate (compound 1.5) and1-methyl-7-(piperidin-4-yl)imidazo[1,5-a]pyridine hydrochloride(compound 66.2) was used in place of 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.2). m/z (ES+) 454 (M+H)⁺.

Compound 73.(4-Cyclopropyl-3-(2,4-dimethyl-1H-imidazol-5-yl)phenyl)(4-(3-methylimidazo[1,5-a]pyridin-7-yl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except methyl 4-cyclopropyl-3-propionylbenzoate (compound 10.7) was usedin place of methyl 2,4-dimethyl-5-propionylbenzoate (compound 1.5) and3-methyl-7-(piperidin-4-yl)imidazo[1,5-a]pyridine hydrochloride(compound 67.2) was used in place of 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.2). m/z (ES+) 454 (M+H)⁺.

Compound 74.1. 1-(4-Bromophenyl)-1H-pyrazole

Into a 100-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was placed a mixture of1-bromo-4-iodobenzene (2.82 g, 9.97 mmol), 1H-pyrazole (680 mg, 9.99mmol), CuI (380 mg, 2.00 mmol), DMEDA (430 μL, 4.00 mmol, 0.40 equiv),Cs₂CO₃ (6.52 g, 20.00 mmol) an CH₃CN (40 mL). The resulting mixture wasstirred overnight at 82° C. After cooling to ambient temperature, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography with ethyl acetate/petroleum ether (1:12) as the eluentto yield the title compound as a white solid (2.1 g, 94%).

Compound 74.5-(4-(4-(1H-Pyrazol-1-yl)phenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 1-(4-bromophenyl)-1H-pyrazole (compound 74.1) was used in placeof 5-bromo-1H-indazole to yield the title compound as a white solid. m/z(ES+) 457 (M+H)⁺.

Compound 75.1. 4-(4-Bromophenyl)-4H-1,2,4-triazole

Into a 100-mL round-bottom flask, was placed a solution of4-bromoaniline (1.71 g, 9.94 mmol), N′-formylformohydrazide (2.64 g,30.0 mmol), and triethylamine (9.74 mL, 69.9 mmol, 7.00 equiv) inpyridine (40 mL). Chlorotrimethylsilane (19.2 mL, 151 mmol) was addeddrop-wise and the resulting solution was stirred for 18 h at 100° C.,then cooled to room temperature. The resulting mixture was concentratedunder reduced pressure and the residue was diluted with brine (50 mL)and extracted with ethyl acetate (6×50 mL). The combined organic layerswere dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The residue was washed with ether (30 mL) and the solids were collectedby filtration to yield the title compound as a pink solid (1.6 g, 72%).

Compound 75.5-(4-(4-(4H-1,2,4-Triazol-4-yl)phenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 4-(4-bromophenyl)-4H-1,2,4-triazole (compound 75.1) was used inplace of 5-bromo-1H-indazole to yield the title compound as a yellowsolid. m/z (ES+) 458 (M+H)⁺.

Compound 76.1. ((4-Bromophenyl)ethynyl)trimethylsilane

Into a 100-mL three neck round-bottom flask, which was maintained withan inert atmosphere of nitrogen, was placed a solution of1-bromo-4-iodobenzene (1.00 g, 3.53 mmol) in tetrahydrofuran/TEA (9:1)(30 mL). PdCl₂(PPh₃)₂ (50 mg, 0.07 mmol), CuI (13.4 mg, 0.07 mmol), andethynyltrimethylsilane (748 μL, 5.29 mmol) were added and the mixturewas stirred for 18 h at room temperature, then concentrated underreduced pressure. The residue was diluted with water (50 mL) andextracted with ethyl acetate (3×20 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with petroleum ether as the eluent to yieldthe title compound as a light yellow solid (0.83 g, 93%).

Compound 76.2. tert-Butyl4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound62.4, except ((4-bromophenyl)ethynyl)trimethylsilane (compound 76.1, 850mg, 3.36 mmol) was used in place of 5-bromo-1H-indazole to yield thetitle compound as a yellow oil (0.80 g, 67%).

Compound 76.3. tert-Butyl 4-(4-ethynylphenyl)piperidine-1-carboxylate

Into a 50-mL round-bottom flask, was placed a solution of tert-butyl4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate (compound76.2, 1.34 g, 3.75 mmol) in tetrahydrofuran (20 mL). Tetrabutylammoniumfluoride (1.95 g, 7.47 mmol) was added and the resulting solution wasstirred for 10 min at room temperature. The mixture was diluted withwater (30 mL) and extracted with EtOAc (3×20 mL). The organic layerswere combined, dried (Na₂SO₄), filtered and concentrated under reducedpressure to yield the title compound as a brown oil (1.0 g, crude).

Compound 76.4. 4-(4-Ethynylphenyl)piperidine hydrochloride

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl4-(4-ethynylphenyl)piperidine-1-carboxylate (compound 76.3, 1.0 g, 3.5mmol) in ethyl acetate (20 mL). Hydrogen chloride (g) was introduced bybubbling through the solution and the resulting solution was stirred for1 hour at room temperature. The solids that formed were collected byfiltration and washed with hexanes (3×10 mL) to yield the title compoundas a brown solid (630 mg, 81%).

Compound 76.2-Cyclobutyl-5-(4-(4-ethynylphenyl)piperidine-1-carbonyl)-N,4-dimethylbenzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 4-(4-ethynylphenyl)piperidine hydrochloride (compound 76.4, 178mg, 0.81 mmol) was used in place of 5-(piperidin-4-yl)-1H-indazole(compound 62.5) to yield the title compound as a white solid (20.1 mg,12%). m/z (ES+) 415 (M+H)⁺.

Compound 77.1. 1-Bromo-4-(prop-1-yn-1-yl)benzene

Into a 250-mL three neck round-bottom flask, which was maintained withan inert atmosphere of nitrogen, was placed 1-bromo-4-iodobenzene (2.00g, 7.07 mmol), PdCl₂(PPh₃)₂ (99.2 mg, 0.14 mmol), CuI (26.8 mg, 0.14mmol), trimethyl(prop-1-yn-1-yl)silane (2.08 mL, 14.1 mmol) andtetrahydrofuran/TEA (9:1) (100 mL). Stirring was initiated andtetrabutylammonium fluoride (3.69 g, 14.1 mmol) was added rapidly to themixture. The resulting mixture was stirred for 18 h at room temperature,then concentrated under reduced pressure. The residue diluted with water(100 mL) and extracted with ethyl acetate (3×50 mL). The organicextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith petroleum ether as the eluent to yield the title compound as alight yellow oil (1.0 g, 73%).

Compound 77.2-Cyclobutyl-N,4-dimethyl-5-(4-(4-(prop-1-yn-1-yl)phenyl)piperidine-1-carbonyl)benzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 1-bromo-4-(prop-1-yn-1-yl)benzene (compound 77.1) was used inplace of 5-bromo-1H-indazole to yield the title compound as a whitesolid. m/z (ES+) 429 (M+H)⁺.

Compound 78.1. Methyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate

To a round-bottom flask was added methyl5-cyano-4-cyclobutyl-2-methylbenzoate (compound 6.4, 3.63 g, 0.015 mol),O,O′-diethyl dithiophosphate (10 mL) and water (1 mL). The reactionmixture was heated to 80° C. for 3 hours (CAUTION: significant gasevolution occurs—this and all other reactions described herein should becarried out in well ventilated fume hoods). After cooling to roomtemperature, the reaction mixture was partitioned between ethyl acetate(50 mL) and water (50 mL). The organic layer was washed successivelywith saturated aqueous NaHCO₃ (50 mL) and brine (50 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel flash chromatography (hexanes/ethyl acetate=80/20to 50/50) to yield the title compound as a yellow solid (3.06 g, 78%yield). m/z (ES+) 264 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.93 (s, 1H),7.82 (s, 1H), 7.26 (s, 1H), 6.92 (s, 1H), 4.19 (m, 1H), 3.89 (s, 3H),2.64 (s, 3H), 2.40 (m, 2H), 2.29-2.15 (m, 2H), 2.12-2.00 (m, 1H),1.95-1.84 (m, 1H).

Compound 78.2. Methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate

To a round-bottom flask was added methyl5-carbamothioyl-4-cyclobutyl-2-methylbenzoate (compound 78.1, 861 mg,3.27 mmol) in THF (10 mL). Iodomethane (400 μL, 6.42 mmol) was addeddrop-wise and the reaction mixture was stirred at room temperature for 7hours. The reaction mixture was concentrated under reduced pressure andthe residue was purified by silica gel flash chromatography (ethylacetate to ethyl acetate/methanol=95/5) to yield the title compound as ayellowish oil (807 mg, 89% yield). m/z (ES+) 278 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆): δ 7.67 (s, 1H), 7.40 (s, 1H), 3.88-3.71 (m, 4H), 2.57 (s,3H), 2.44 (s, 3H), 2.22-2.19 (m, 2H), 2.12 (m, 2H), 1.98-1.86 (m, 1H),1.82-1.70 (m, 1H).

Compound 78.3. Methyl4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate

To a round-bottom flask was added methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate (compound78.2, 556 mg, 2.00 mmol) and acetohydrazide (223 mg, 3.00 mol) in aceticacid (6 mL). The mixture was heated at 90° C. for 3 hours then cooled toroom temperature. The reaction mixture was partitioned between water (50mL) and ethyl acetate (50 mL) and the organic layer was washed withbrine (2×50 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography (hexanes/ethyl acetate=50/50 to 30/70) to yield thecompound as a white solid (243 mg, 43% yield). m/z (ES+) 286 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 7.32 (s, 1H), 4.24-4.05 (m, 1H),3.89 (s, 3H), 2.69 (s, 3H), 2.54 (s, 3H), 2.23-2.20 (m, 2H), 2.16-2.05(m, 2H), 2.05-1.88 (m, 1H), 1.88-1.71 (m, 1H).

Compound 78.4.4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid

To a solution of methyl4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate(compound 78.3, 240 mg, 0.842 mmol) in methanol (5 mL) was added aqueousNaOH (6 mL, 1 M). The resulting mixture was heated to 50° C. for 6 hoursthen cooled to ambient temperature and acidified to pH 2 with aqueous 1M HCl and extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with brine (50 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield the title compound as awhite solid (260 mg, quantitative). m/z (ES+) 272 (M+H)⁺.

Compound 78.5. 6-(Piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1.2except 6-bromoimidazo[1,2-a]pyridine (500 mg) was used in place of4-bromobenzonitrile to yield the title compound as a brown solid (400mg, 66% over 2 steps).

Compound 78.(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)(4-(imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoicacid (compound 78.4, 100 mg) was used in place of4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3)and 6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride (compound78.5, 88 mg) was used in place of 5-(piperidin-4-yl)-1H-indazole(compound 62.5). The title compound was obtained as a white solid (35.6mg, 21%). m/z (ES+) 455 (M+H)⁺.

Compound 79.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 62,except 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoicacid (compound 78.4) was used in place of4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3)and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4)was used in place of 5-(piperidin-4-yl)-1H-indazole (compound 62.5). m/z(ES+) 430 (M+H)⁺.

Compound 80.1. 3-Methoxypropanehydrazide

Into a 500-mL round-bottom flask, was placed a solution of methyl3-methoxypropanoate (30.0 g, 254 mmol) in ethanol (100 mL) and hydrazinehydrate (24.7 mL, 507 mmol). The resulting solution was stirredovernight at 80° C., then cooled and concentrated under reduced pressureto yield 26.3 g (88%, crude) of the title compound as colorless oil.

Compound 80.4-(1-(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 78,except 3-methoxypropanehydrazide (compound 80.1) was used in place ofacetohydrazide and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride (compound 78.5).m/z (ES+) 474 (M+H)⁺.

Compound 81.4-(1-(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 78,except 3-methoxypropanehydrazide (compound 80.1) was used in place ofacetohydrazide and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound5.2) was used in place of 6-(piperidin-4-yl)imidazo[1,2-a]pyridinehydrochloride (compound 78.5). m/z (ES+) 456 (M+H)⁺.

Compound 82.1. 1-tert-Butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100mmol) in diethylether (60 mL) under nitrogen at −30° C., was addeddrop-wise a solution of BF₃.Et₂O (16.0 mL, 130 mmol) in ether (20 mL).After stirring for 30 min at −30° C., a solution of ethyl 2-diazoacetate(16.0 g, 140 mmol) in ether (20 mL) was added drop-wise to the reactionat −30° C. The resulting solution was stirred for 1 h at −30° C., thenat room temperature for 2 h. The reaction was carefully quenched with30% aqueous potassium carbonate (100 mL) and the resulting mixture wasextracted with ethyl acetate (2×250 mL). The combined organic extractswere washed with brine (2×50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with ethylacetate/petroleum ether (1/10) as the eluent to furnish 19 g (66%) ofthe title compound as a light yellow oil.

Compound 82.2. tert-Butyl 4-oxoazepane-1-carboxylate

To a solution 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate(compound 82.1, 19.0 g, 66.6 mmol) in 1,4-dioxane (190 mL) was addeddrop-wise a solution of sodium hydroxide (4.00 g, 100 mmol) in water(100 mL). The resulting mixture was stirred at room temperatureovernight. The pH was then adjusted to 4-5 with hydrogen chloride (aq. 3M) and the resulting solution was extracted with ethyl acetate (2×50mL). The combined organic extracts were washed with brine (2×10 mL),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by silica gel columnchromatography using ethyl acetate/petroleum ether (1:3) as the eluentto furnish 11 g (77%) of the title compound as a yellow oil.

Compound 82.3. tert-Butyl 4-bromo-5-oxoazepane-1-carboxylate

To a solution tert-butyl 4-oxoazepane-1-carboxylate (compound 82.2, 11.0g, 51.6 mmol) in chloroform (220 mL) at 0° C. was added drop-wise asolution of bromine (3.98 mL, 77.6 mmol) in chloroform (110 mL). Theresulting mixture was stirred at room temperature overnight, then thesolids that formed were collected by filtration and dissolved indichloromethane (200 mL). Triethylamine (16.8 mL, 121 mmol) and (Boc)₂O(8.70 g, 40.3 mmol) were added to the mixture at 0° C. and the resultingsolution was stirred for 3 h at room temperature, and then concentratedunder reduced pressure. The crude residue was purified by silica gelchromatography using ethyl acetate/petroleum ether (1:10) as the eluentto give 4.0 g (27%) of the title compound as a yellow oil.

Compound 82.4. 4-Cyclobutyl-5-formyl-2-methylbenzoic acid

Into a three neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution of4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 62.1, 5.00 g, 80%,12.7 mmol) in a solvent mixture of tetrahydrofuran and Et₂O (50 mL/50mL). The solution was cooled to −78° C. then n-butyllithium (15 mL, 2.5M in hexanes) was added drop-wise with stirring. N,N-Dimethylformamide(2.64 mL, 34.2 mmol) was added and the resulting mixture was stirred for1 h at −78° C., then carefully quenched by slow addition of aqueousNH₄Cl (sat., 50 mL). The pH was adjusted to 1-2 with aqueous hydrogenchloride (6 M), then diluted with ethyl acetate (100 mL) and washed withbrine (4×50 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified using silica gel column chromatography with ethylacetate/petroleum ether (1:1) as the eluent to furnish 1.62 g (41%) ofthe title compound as a white solid.

Compound 82.5. Methyl 4-cyclobutyl-5-formyl-2-methylbenzoate

Into a 100-mL round-bottom flask, was placed a mixture of4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 82.4, 500 mg, 2.29mmol) in N,N-dimethylformamide (10 mL) and sodium bicarbonate (390 mg,4.64 mmol). With stirring, methyl iodide (430 μL, 6.90 mmol) was addeddrop-wise and the resulting mixture was stirred for 5 h at roomtemperature. The reaction was then diluted with EtOAc (50 mL) and themixture was washed with brine (4×10 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure to yield0.40 g (crude) of the title compound as a brown oil

Compound 82.6. tert-Butyl2-(2-cyclobutyl-5-(methoxycarbonyl)-4-methylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate

Into a 100-mL round-bottom flask, was placed a mixture of methyl4-cyclobutyl-5-formyl-2-methylbenzoate (compound 82.5, 300 mg, 1.29mmol), ammonium acetate (449 mg, 5.83 mmol), tert-butyl4-bromo-5-oxoazepane-1-carboxylate (compound 82.3, 564 mg, 1.93 mmol)and ammonium hydroxide (25%)(597 μL, 3.87 mmol) in N,N-dimethylformamide(8 mL). The resulting mixture was stirred for 4 h at 130° C., thencooled and quenched with water/ice (10 mL). The aqueous phase wasextracted with ethyl acetate (2×30 mL) and the combined organic layerswere washed with brine (3×10 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with ethyl acetate/petroleum ether (1/1) asthe eluent to yield 0.10 g (18%) of the title compound as a white solid.

Compound 82.7. Methyl4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoatehydrochloride

Into a 50-mL 3-necked round-bottom flask, was placed a solution oftert-butyl2-(2-cyclobutyl-5-(methoxycarbonyl)-4-methylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate(compound 82.6, 200 mg, 0.46 mmol) in EtOAc (10 mL). Hydrogen chloride(gas) was introduced into the solution by bubbling and the solution wasstirred for 30 min at room temperature. The resulting mixture wasconcentrated under reduced pressure to yield 136 mg (crude) of the titlecompound as a yellow solid.

Compound 82.8. Methyl4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate

Into a 100-mL round-bottom flask, was placed a mixture of methyl4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoatehydrochloride (compound 82.7, 40 mg, 0.11 mmol), NaBH(OAc)₃ (75 mg, 0.35mmol), and formaldehyde (37 wt %) (26 μL, 0.33 mmol) in tetrahydrofuran(4 mL). The resulting mixture was stirred for 2 h at 40° C., then cooledand the pH of the solution was adjusted to 8-9 with sodium bicarbonate(sat.). The aqueous phase was extracted with ethyl acetate (2×20 mL) andthe combined organic layers were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield 20 mg (crude) of the titlecompound as a yellow solid.

Compound 82.9.4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoicacid

Into a 50-mL round-bottom flask, was placed a mixture of methyl4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate(compound 82.8, 40 mg, 0.11 mmol) and NaOH (18 mg, 0.44 mmol) inmethanol (4 mL), water (2 mL). The resulting solution was stirred for 2h at 60° C. After cooling to room temperature, the volatiles wereremoved under reduced pressure. The pH of the residual solution wasadjusted to about 1 with hydrogen chloride (3 M) and concentrated underreduced pressure to yield 0.10 g (crude) of the title product as the HClsalt as a yellow solid.

Compound 82.4-(1-(4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

Into a 100-mL round-bottom flask, was placed a mixture of4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoicacid (compound 82.9, 40 mg, 0.12 mmol), EDC.HCl (45.4 mg, 0.24 mmol,2.00 equiv), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 23 mg, 0.12mmol) in N,N-dimethylformamide (5 mL). The resulting solution wasstirred for 4 h at room temperature then quenched by the addition ofwater/ice (10 mL). The resulting mixture was extracted with ethylacetate (2×20 mL) and the combined organic layers were washed with brine(2×10 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield the crude product which waspurified by Prep-HPLC using the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; mobile phase, WATER WITH 0.03% NH4OH and CH3CN (30% CH3CNup to 43% in 8 min, up to 100% in 4 min, down to 30% in 2 min);Detector, Waters 2489, 254 & 220 nm. The fractions containing cleanproduct were combined to yield 2.2 mg (4%) of the title compound as awhite solid. m/z (ES+) 480 (M+H)⁺.

Compound 83.1. 5-Formyl-2,4-dimethylbenzoic acid

To a stirred solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3,5.00 g, 18.1 mmol) in tetrahydrofuran (150 mL) under nitrogen at −78° C.was added n-BuLi (2.5 M in THF, 18 mL, 45 mmol) drop-wise. The mixturewas stirred at −78° C. for 1 h and then DMF (5.3 mL, 68 mmol) was addeddrop-wise. The resulting mixture was stirred at −78° C. for 0.5 h andthen carefully quenched by slow addition of water (50 mL). The pH of themixture was adjusted to ˜3-4 with aqueous HCl (6 M) and then extractedwith ethyl acetate (3×200 mL). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified using silica gel column chromatography with ethylacetate/petroleum ether (1:10-1:5) as the eluent to yield the titlecompound as a white solid (2.4 g, 74%).

Compound 83.2. Methyl 5-formyl-2,4-dimethylbenzoate

Into a 250-mL round-bottom flask, was placed5-formyl-2,4-dimethylbenzoic acid (compound 83.1, 2.00 g, 11.2 mmol) andmethanol (50 mL). Concentrated sulfuric acid (2 mL) was carefully addeddrop-wise and the resulting solution was stirred for 2 h at 80° C., thencooled and the volatiles were removed under reduced pressure. The pH ofthe residue was adjusted to 9 with sodium bicarbonate (sat.), then theaqueous phase was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine (2×20 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure to yield 2.0 g (crude)of the title compound as yellow oil. The crude product was used in nextstep without further purification.

Compound 83.3. tert-Butyl2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate

Into a 10-mL sealed tube, was placed methyl5-formyl-2,4-dimethylbenzoate (compound 83.2, 500 mg, 2.60 mmol),tert-butyl 4-bromo-5-oxoazepane-1-carboxylate (compound 82.3, 1.1 g, 3.8mmol), ammonium hydroxide (25%) (1.2 mL, 7.8 mmol), ammonium acetate(900 mg, 11.7 mmol) in N,N-dimethylformamide (6 mL). The resultingmixture was stirred for 3 h at 130° C. behind a blast shield, thencooled to room temperature and diluted with ethyl acetate (150 mL). Themixture was washed with brine (5×20 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with dichloromethane/methanol (10:1) as theeluent to yield 0.80 g (46%) of the title compound as yellow oil.

Compound 83.4. Methyl5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate(compound 83.3, 800 mg, 2.00 mmol) in dichloromethane (16 mL).Trifluoroacetic acid (4 mL) was added drop-wise and the resultingsolution was stirred for 5 h at room temperature. The pH of the solutionwas carefully adjusted to 8-9 with NaHCO₃ (sat.) and the aqueous phasewas extracted with DCM (3×30 mL), and the combined organics were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to yield0.60 mg (crude) of the title compound as brown oil.

Compound 83.5. Methyl5-(6-isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate

Into a 100-mL round-bottom flask, was placed methyl5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate(compound 83.4, 347 mg, 0.84 mmol), 2-bromopropane (790 μL, 8.40 mmol),N,N-diisopropylethylamine (1.46 mL, 8.4 mmol) in N,N-dimethylformamide(5 mL). The solution was stirred for 4 h at 80° C., then cooled to roomtemperature. The resulting solution was diluted with ethyl acetate (50mL) and washed with brine (4×20 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield 0.22 g (crude) of the titlecompound as brown oil.

Compound 83.4-(1-(5-(6-Isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 82,except methyl5-(6-isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate(compound 83.5) was used in place of4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate(compound 82.8). m/z (ES+) 468 (M+H)⁺.

Compound 84.4-(1-(2,4-Dimethyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 82,except methyl5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate(compound 83.4) was used in place of methyl4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoatehydrochloride (compound 82.7). m/z (ES+) 440 (M+H)⁺.

Compound 85.1. 3-(4-Chlorophenyl)azetidine hydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.2, except (4-chlorophenyl)boronic acid was used in place of(4-cyanophenyl)boronic acid. The title compound was obtained in 20%yield over two steps.

Compound 85.(3-(4-Chlorophenyl)azetidin-1-yl)(2,4-dimethyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)phenyl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 82,except methyl5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate(compound 83.4) was used in place of methyl4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoatehydrochloride (compound 82.7) and 3-(4-chlorophenyl)azetidinehydrochloride (compound 85.1) was used in place of4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+)449 (M+H)⁺.

Compound 86.1. Methyl 4-cyclopropyl-2-methylbenzoate

To a solution of methyl 4-bromo-2-methylbenzoate (compound 6.1, 5.00 g,20.7 mmol, 95%) in a mixture of toluene and H₂O (20 mL/1 mL) were addedpotassium carbonate (6.10 g, 44.1 mmol), cyclopropylboronic acid (2.30g, 26.8 mmol), Pd(dppf)Cl₂ (900 mg, 1.23 mmol), and Pd(OAc)₂ (250 mg,1.12 mmol). The reaction mixture was purged with nitrogen and stirred at80° C. overnight. After cooling to room temperature, the mixture wasthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography with ethylacetate/petroleum ether (1:50) as the eluent to yield 2.68 g (61%) ofthe title compound as a colorless oil.

Compound 86.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate

To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 86.1,2.68 g, 13.4 mmol, 95%) in AcOH (50 mL) were added NaIO₄ (1.51 g, 7.08mmol), iodine (3.58 g, 14.1 mmol), and sulfuric acid (106 μL, 2.0 mmol,0.15 equiv). The reaction mixture was stirred overnight at 110° C. Aftercooling to ambient temperature, water (100 mL) was slowly added and themixture was extracted with ethyl acetate (100 mL). The organic layer waswashed with Na₂S₂O₃ (aq., sat., 3×30 mL) and brine (30 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1/50) as the eluent to yield 2.0 g (45%) of thetitle compound as a colorless oil.

Compound 86.3. 4-Cyclopropyl-5-iodo-2-methylbenzoic acid

Into a 500-mL round-bottom flask, was placed a solution of methyl4-cyclopropyl-5-iodo-2-methylbenzoate (compound 86.2, 15.0 g, 47.5 mmol)in methanol (150 mL). A solution of sodium hydroxide (5.70 g, 143 mmol)in water (75 mL) was added and the resulting solution was stirred for 4h at 60° C., then cooled to room temperature. The volatiles were removedunder reduced pressure and the remaining solution was adjusted to pH 3with aqueous hydrogen chloride (12 M). The mixture was extracted withethyl acetate (2×200 mL) and the combined organic extracts were washedwith NH₄Cl (aq.) (2×400 mL) and brine (400 mL). The organic layer wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure toyield 13.0 g (91%) of the title compound as a light yellow solid.

Compound 86.4. Methyl4-cyclopropyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound83.4, except 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3)was used in place of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).

Compound 86.4-(1-(4-Cyclopropyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 82,except methyl4-cyclopropyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoate(compound 86.4) was used in place of methyl4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoatehydrochloride (compound 82.7). m/z (ES+) 466 (M+H)⁺.

Compound 87.1. Methyl 4-cyclopropyl-5-formyl-2-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound83.2, except 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3)was used in place of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).

Compound 87.2. Methyl4-cyclopropyl-5-(3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoate

Into a 100-mL round-bottom flask was placed a mixture of methyl4-cyclopropyl-5-formyl-2-methylbenzoate (compound 87.1, 500 mg, 2.29mmol), pyridine-3,4-diamine (500 mg, 4.58 mmol), NH₄OAc (1.42 g, 18.4mmol) and ethanol (50 mL). The resulting mixture was stirred open to theair for 3 days at 70° C., then cooled to room temperature and dilutedwith aqueous sodium bicarbonate (sat., 50 mL). The aqueous phase wasextracted with ethyl acetate (2×50 mL) and the combined organic layerswere dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography with ethylacetate as the eluent to yield 268 mg (38%) of the title compound as ayellow semi-solid.

Compound 87.3.2-(2-Cyclopropyl-5-(methoxycarbonyl)-4-methylphenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-5-iumiodide

Into a 50-mL round-bottom flask, was placed a solution of methyl4-cyclopropyl-5-(3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoate(compound 87.2, 500 mg, 1.63 mmol) in dichloromethane (15 mL).Iodomethane (203 μL, 3.26 mmol) was added drop-wise and the resultingsolution was stirred overnight at room temperature. The mixture wasconcentrated under reduced pressure to yield 0.30 g (41%) of the titlecompound as a yellow solid.

Compound 87.4. Methyl4-cyclopropyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate

Into a 100-mL round-bottom flask, was placed a mixture of2-(2-cyclopropyl-5-(methoxycarbonyl)-4-methylphenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-5-iumiodide (compound 87.3, 300 mg, 0.67 mmol) and NaBH₄ (1.42 g, 37.5 mmol)in methanol (30 mL). The resulting mixture was stirred for 4 h at roomtemperature, then concentrated under reduced pressure. The residue wasdiluted with EtOAc (120 mL) and the mixture was washed with brine (2×40mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography withEtOAc/MeOH (20/1) as the eluent to yield 170 mg (78%) the title compoundas a light yellow oil.

Compound 87.4-(1-(4-Cyclopropyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 82,except methyl4-cyclopropyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate(compound 87.4) was used in place of4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate(compound 82.8). m/z (ES+) 452 (M+H)⁺.

Compound 88.1. Methyl4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound87.4, except methyl 4-cyclobutyl-5-formyl-2-methylbenzoate (compound82.5) was used in place of methyl4-cyclopropyl-5-formyl-2-methylbenzoate (compound 87.1).

Compound 88.4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 82,except methyl4-cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoate(compound 88.1) was used in place of4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoate(compound 82.8). m/z (ES+) 466 (M+H)⁺.

Compound 89.1. Methyl 2-bromo-4-methylbenzoate

A solution of 2-bromo-4-methylbenzoic acid (10.0 g, 46.5 mmol) in MeOH(50 mL) was cooled to 0° C., then concentrated sulfuric acid (10 mL) wascarefully added. The mixture was heated at 70° C. for 2 hours. Aftercooling to room temperature, the volatile organics were removed underreduced pressure, and the residue was poured onto ice-water (100 mL).The mixture was extracted with EtOAc (×2) and the combined organicextracts were washed with aq. NaHCO₃, brine, dried (MgSO₄), filtered,and concentrated to yield 10.5 g (99%) of the title compound as a clearoil. ¹H NMR (400 MHz, Chloroform-d) δ 7.73 (d, 1H), 7.50 (d, 1H),7.19-7.11 (m, 1H), 3.92 (s, 3H), 2.36 (s, 3H).

Compound 89.2. Methyl 2-cyclobutyl-4-methylbenzoate

Cyclobutylzinc(II) bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added toa mixture of methyl 2-bromo-4-methylbenzoate (compound 89.1, 5.0 g, 21.8mmol) and PdCl₂(dppf)CH₂Cl₂ (1.78 g, 2.20 mmol). The mixture wasdegassed with argon, then heated at 65° C. under argon for 24 hours. Themixture was cooled to 0° C., then carefully quenched with water (10 mL).The mixture was diluted with EtOAc (200 mL) and washed with water thenbrine. The organic layer was dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexanes:EtOAc 30:1 to 20:1) to yield 3.6 g (81%) of thetitle compound. ¹H NMR (400 MHz, Chloroform-d) δ 7.68 (d, 1H), 7.23-7.17(s, 1H), 7.03 (d, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 2.39 (s, 3H), 2.34(m, 2H), 2.16-1.96 (m, 3H), 1.80 (m, 1H).

Compound 89.3. Methyl 2-cyclobutyl-5-iodo-4-methylbenzoate

To a solution methyl 2-cyclobutyl-4-methylbenzoate (compound 89.2, 4.77g, 23.3 mmol) in concentrated sulfuric acid (100 mL) at 0° C., was addedN-iodosuccinimide (5.25 g, 23.3 mmol) portion-wise. The mixture wasstirred at 0° C. for 30 min and then at RT for 2 hours. The thick, darkmixture was cooled back to 0° C., then MeOH (100 mL) was added slowlyand carefully. The mixture was heated at 60° C. for 2 hours. Aftercooling to room temperature, the volatile solvents were removed underreduced pressure and the residue was carefully poured onto ice water(200 mL). The mixture was extracted with EtOAc (2×) and the combinedorganic extracts were washed with brine, aqueous NaHCO₃ (1 M), dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexanes:EtOAc 30:1 to20:1) to yield 5.0 g (65%) of the title compound as a clear oil. ¹H NMR(400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.24 (s, 1H), 4.17-4.04 (m, 1H),3.86 (s, 3H), 2.48-2.44 (s, 3H), 2.40-2.28 (m, 2H), 2.13-1.92 (m, 3H),1.85-1.75 (m, 1H).

Compound 89.4. Methyl 5-cyano-2-cyclobutyl-4-methylbenzoate

A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (compound 89.3,3.0 g, 9.1 mmol), Zn(CN)₂ (2.3 g, 19.6 mmol) and Pd(PPh₃)₄ (0.55 g, 0.47mmol) in DMF (50 mL) was degassed and the system was charged with argon.The mixture was heated at 100° C. overnight, then cooled to roomtemperature. The mixture was quenched with saturated aqueous FeSO₄ (20mL), then diluted with EtOAc (200 mL). The solids were removed byfiltration through Celite® and the filtrate was partitioned betweenwater and EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexanes:EtOAc 30:1 to20:1) to yield 2.0 g (96%) of the title compound. ¹H NMR (400 MHz,Chloroform-d) δ 8.03 (s, 1H), 7.34 (s, 1H), 4.26-4.13 (m, 1H), 3.89 (s,3H), 2.59 (s, 3H), 2.46-2.32 (m, 2H), 2.16-1.98 (m, 3H), 1.90-1.78 (m,1H).

Compound 89.5. 5-Cyano-2-cyclobutyl-4-methylbenzohydrazide

To a solution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (compound89.4, 2.0 g, 8.73 mmol) in EtOH (10 mL) was added anhydrous hydrazine (2mL, excess) at room temperature. The mixture was heated at 90° C.overnight, then the mixture was cooled to room temperature andpartitioned between water (60 mL) and EtOAc (200 mL). The organic layerwas washed with water (×2), brine, dried (Na₂SO₄), filtered, andconcentrated to yield 1.9 g (95%) of the title compound as a whitesolid. m/z (ES+) 230 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.52 (s,1H), 7.32 (s, 1H), 6.91 (br, 1H), 4.08 (br, 2H), 3.89 (m, 1H), 2.61-2.52(m, 3H), 2.42-2.28 (m, 2H), 2.18-1.98 (m, 3H), 1.91-1.78 (m, 1H).

Compound 89.6.5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile

To a solution of 5-cyano-2-cyclobutyl-4-methylbenzohydrazide (compound89.5, 0.5 g, 2.18 mmol) in H₂O (10 mL) and dioxane (15 mL) was addedNaHCO₃ (0.55 g, 6.55 mmol). After the mixture was stirred at roomtemperature for 5 minutes, BrCN (1.3 mL, 5 M in CH₃CN, 6.55 mmol) wasadded drop-wise. The mixture was stirred at room temperature for 30minutes, where upon white solids formed. The mixture was diluted withEtOAc and washed with water, then brine. The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexanes:EtOAc 1:1 toEtOAc) to yield 0.55 g (theoretical) of the title compound as a whitesolid. m/z (ES+) 255 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.93 (s,1H), 7.45 (s, 1H), 5.10 (br, 2H), 4.38 (m, 1H), 2.61 (s, 3H), 2.48-2.34(m, 2H), 2.17-1.98 (m, 3H), 1.91-1.79 (m, 1H).

Compound 89.7.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile

To a solution of5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile(compound 89.6, 0.5 g, 2.0 mmol) in MeOH (40 mL) was added KOH (1.11 g,20.0 mmol). The mixture was heated at 85° C. overnight, then cooled to0° C. and neutralized to pH 7 with aqueous 1 M HCl. The mixture wasextracted with EtOAc (×2), and the combined organic extracts were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexanes:EtOAc 1:1 toEtOAc) to yield 0.2 g (34%) of the title compound as a white solid. m/z(ES+) 269 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.96 (br, 1H), 7.82(s, 1H), 7.35 (s, 1H), 4.11 (s, 3H), 4.15-4.05 (m, 1H), 2.59 (s, 3H),2.31-2.16 (m, 2H), 2.14-1.89 (m, 3H), 1.87-1.71 (m, 1H).

Compound 89.8.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide

To a solution of4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile(compound 89.7, 0.15 g, 0.53 mmol) in EtOH (10 mL) was added NH₄OH (0.18mL, 2.66 mmol, 14.8 M in H₂O), followed by H₂O₂ (1.8 mL, 26.6 mmol, 50%in H₂O). The mixture was stirred at room temperature overnight, thencooled to 0° C. and carefully quenched with 1 M Na₂S₂O₃ solution (26mL). The mixture was extracted with EtOAc (×2) and the combined organicextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by prep-TLC (5% MeOH in CH₂Cl₂) toyield 0.1 g (63%) of the title compound as a white solid. m/z (ES+) 287(M+H)⁺. ¹H NMR (400 MHz, Methanol-d4) δ 7.50 (s, 1H), 7.33 (s, 1H), 4.03(s, 3H), 3.95-4.05 (m, 1H), 2.51 (s, 3H), 2.23-2.11 (m, 2H), 2.11-1.88(m, 3H), 1.83-1.71 (m, 1H).

Compound 89.94-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid

To a solution of4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide(compound 89.8, 0.1 g, 0.33 mmol) in TFA (5 mL) at 0° C., was addedNaNO₂ (46 mg, 0.66 mmol). The mixture was stirred at 0° C. for 1 hour,then at room temperature for 2 hours. The mixture was concentrated underreduced pressure and the residue was partitioned between EtOAc andbrine. The aqueous layer was extracted with EtOAc and the combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure to yield 0.1 g (theoretical) of the title compound as aclear oil. m/z (ES+) 288 (M+H)⁺.

Compound 89.4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 89.9) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 428 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 13.63-13.17 (br, 1H),7.83 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.49 (s, 1H), 7.39 (s,1H), 4.48 (m, 1H), 4.32 (m, 1H), 4.15 (m, 1H), 4.07-3.95 (m, 3H), 3.93(s, 3H), 2.41 (s, 3H), 2.21-2.11 (m, 2H), 2.06-1.97 (m, 2H), 1.94-1.84(m, 1H), 1.78-1.68 (m, 1H).

Compound 90.4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 89.9) and 4-(3-fluoroazetidin-3-yl)benzonitrilehydrochloride (compound 43.4) were used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2),respectively. m/z (ES+) 446 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ13.64-13.05 (br, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H),7.56 (s, 1H), 7.41 (s, 1H), 4.61-4.38 (m, 4H), 4.19 (m, 1H), 3.92 (s,3H), 2.42 (s, 3H), 2.16 (m, 1H), 2.02 (m, 1H), 1.89 (m, 1H), 1.75 (m,1H).

Compound 91.1. Methyl4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound86.2, 4.0 g, 12.7 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.86 g,15.2 mmol), PdCl₂(dppf)CH₂Cl₂ (0.52 g, 0.64 mmol) and potassium acetate(3.73 g, 38.10 mmol) in DMSO (50 mL) was degassed with argon. Themixture was heated at 80° C. for 18 hours under argon, then cooled toroom temperature and diluted with ethyl acetate (300 mL). The mixturewas washed with water, aqueous HCl (1 M), saturated aqueous NaHCO₃, andbrine, then dried (MgSO₄), filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexanes:EtOAc 50:1 to 30:1) to yield 2.63 g (65.6%) of the titlecompound as a white solid. m/z (ES+) 317 (M+H)⁺.

Compound 91.2. 4-Benzyl-3,5-dibromo-4H-1,2,4-triazole

To a solution of 3,5-dibromo-4H-1,2,4-triazole (3.0 g, 13.3 mmol) in DMF(10 mL) at 0° C. was added NaH (60% in mineral oil, 0.58 g, 14.5mmol)(CAUTION: NaH and DMF can become a runaway reaction. All necessarysafety precautions were performed). After the mixture was stirred at 0°C. for 30 minutes, benzyl bromide (1.57 mL, 13.2 mmol) was added. Themixture was stirred at 0° C. for 2 hours, then the mixture waspartitioned between EtOAc (150 mL) and water (30 mL). The organic layerwas washed with brine (2×30 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexanes:EtOAc 50:1 to 10:1) to yield 3.71 g(89%) of the title compound as a white solid. m/z (ES+) 316, 318, 320(M+H)⁺.

Compound 91.3. 4-Benzyl-3-bromo-5-methoxy-4H-1,2,4-triazole

To a solution of 4-benzyl-3,5-dibromo-4H-1,2,4-triazole (compound 91.2,3.71 g, 11.7 mmol) in MeOH 15 mL) was added NaOMe (1.26 g, 23.4 mmol)and the mixture was refluxed for 18 hours. The mixture was cooledsomewhat and additional NaOMe was added (1.26 g, 23.4 mmol). The mixturewas refluxed for an additional 5 hours, then cooled to room temperature,and the solvent was removed under reduced pressure. The residue wasdissolved in EtOAc (200 mL) and washed with water (30 mL). The organiclayer was dried (MgSO₄), filtered and concentrated under reducedpressure to yield 3.13 g (theoretical) of the title compound as a clearoil. m/z (ES+) 269 (M+H)⁺.

Compound 91.4. Methyl5-(4-benzyl-5-methoxy-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoate

A mixture of 4-benzyl-3-bromo-5-methoxy-4H-1,2,4-triazole (compound91.3, 1.2 g, 4.48 mmol), methyl4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 91.1, 1.56 g, 4.93 mmol), PdCl₂(dppf)CH₂Cl₂ (0.37 g, 0.45mmol) and potassium carbonate (3.10 g, 22.5 mmol) in dioxane (50 mL) andwater (20 mL) was degassed with argon. The mixture was heated at 90° C.for 18 hours under argon, then cooled to room temperature. The mixturewas diluted with ethyl acetate (300 mL) and washed with water thenbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexanes:EtOAc 10:1 to 4:1) to yield 1.51 g (89%) of the title compoundas thick oil. m/z (ES+) 378 (M+H)⁺.

Compound 91.5. Methyl4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoate

A flask containing methyl5-(4-benzyl-5-methoxy-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoate(compound 91.4, 0.55 g, 1.46 mmol) and Pd/C (10%, 0.25 g) was purgedwith nitrogen, then MeOH (10 mL) and HCl (4 M in dioxane, 37 μL, 0.15mmol) were carefully added. The system was then charged with hydrogenand the mixture was stirred at room temperature for 3 hours. Uponcompletion, the system was purged with nitrogen, then the mixture wasneutralized with a few drops of NH₄OH and filtered through Celite®. Thefiltrate was concentrated under reduced pressure and the residue waspurified using prep-TLC (hexanes:EtOAc 1:1) to yield 0.3 g (71%) of thetitle compound as a clear oil. m/z (ES+) 288 (M+H)⁺.

Compound 91.6.4-Cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoate(compound 91.5) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 274 (M+H)⁺.

Compound 91.4-(1-(4-Cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 91.6) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 414 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 13.84-12.92 (br, 1H),7.86-7.80 (m, 2H), 7.61-7.53 (m, 3H), 6.85 (s, 1H), 4.47 (m, 1H), 4.32(m, 1H), 4.08-3.94 (m, 3H), 2.79 (m, 1H), 0.94 (m, 2H), 0.70 (n, 2H).

Compound 92.4-(1-(4-Cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 91.6) and 4-(3-fluoroazetidin-3-yl)benzonitrile (compound43.4) were used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2),respectively. m/z (ES+) 432 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ13.66-13.01 (br, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H),7.61 (s, 1H), 6.86 (s, 1H), 4.60-4.38 (m, 4H), 3.91 (s, 3H), 2.82 (m,1H), 2.34 (s, 3H), 0.94 (m, 2H), 0.71 (m, 2H).

The compounds in TABLE 5 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 78 and 79.

TABLE 5 m/z (ES+) Cpd Name Structure (M + H)⁺  96 4-(1-(4-((1S,3S)-3-methoxycyclobutyl)- 2-methyl-5-(5- methyl-4H-1,2,4- triazol-3-yl)benzoyl)piperidin- 4-yl)benzonitrile

470  97 4-(1-(4-((1R,3R)-3- methoxycyclobutyl)- 2-methyl-5-(5-methyl-4H-1,2,4- triazol-3- yl)benzoyl)piperidin- 4-yl)benzonitrile

470  98 4-(1-(4-((1S,3S)-3- hydroxycyclobutyl)- 2-methyl-5-(5-methyl-4H-1,2,4- triazol-3- yl)benzoyl)piperidin- 4-yl)benzonitrile

456 104 4-(1-(4-((1R,3R)-3- hydroxycyclobutyl)- 2-methyl-5-(5-methyl-4H-1,2,4- triazol-3- yl)benzoyl)piperidin- 4-yl)benzonitrile

456 107 4-(1-(4-((1S,3S)-3- fluorocyclobutyl)-2- methyl-5-(5-methyl-4H-1,2,4-triazol-3- yl)benzoyl)piperidin- 4-yl)benzonitrile

458 108 4-(1-(4-((1R,3R)-3- fluorocyclobutyl)-2- methyl-5-(5-methyl-4H-1,2,4-triazol-3- yl)benzoyl)piperidin- 4-yl)benzonitrile

458 112 4-(1-(2-methyl-5-(5- methyl-4H-1,2,4- triazol-3-yl)-4-(tetrahydrofuran-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

456

The compounds in TABLE 6 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 89, 90, 91, and 92.

TABLE 6 m/z (ES+) Cpd Name Structure (M + H)⁺  99 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethoxy)- 4H-1,2,4-triazol-3-yl)-2- methylbenzoyl)piperidin-4-yl)benzonitrile

500 100 4-(1-(4-cyclobutyl-5- (5-(2-hydroxyethoxy)-4H-1,2,4-triazol-3-yl)-2- methylbenzoyl)piperidin- 4-yl)benzonitrile

486 133 4-(1-(4-cyclopropyl-5- (5-methoxy-4H-1,2,4- triazol-3-yl)-2-methylbenzoyl)-4- fluoropiperidin-4- yl)benzonitrile

460 134 4-(1-(4-cyclopropyl-5- (5-methoxy-4H-1,2,4- triazol-3-yl)-2-methylbenzoyl)piperidin- 4-yl)benzonitrile

442 137 4-(1-(4-cyclopropyl-2- ethyl-5-(5-methoxy- 4H-1,2,4-triazol-3-yl)benzoyl)azetidin-3- yl)benzonitrile

428 138 4-(1-(4-cyclopropyl-2- ethyl-5-(5-methoxy- 4H-1,2,4-triazol-3-yl)benzoyl)-3- fluoroazetidin-3- yl)benzonitrile

446

The compounds in TABLE 7 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 62, 63 and 64.

TABLE 7 m/z (ES+) Cpd Name Structure (M + H)⁺ 103 5-(4-(4-cyanophenyl)piperidine- 1-carbonyl)-2- cyclobutyl-4- methylbenzamide

402 106 2-cyclobutyl-5-(4- (imidazo[1,2-a]pyridin- 7-yl)piperidine-1-carbonyl)-N,4- dimethylbenzamide

431 110 2-cyclobutyl-5-(4- (imidazo[1,2-a]pyridin- 6-yl)piperidine-1-carbonyl)-N,4- dimethylbenzamide

431 116 5-(4-(benzofuran-7- yl)piperidine-1- carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide

431

The compounds in TABLE 8 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 78, 79, 80 and 81.

TABLE 8 m/z (ES+) Cpd Name Structure (M + H)⁺ 111 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl- 4H-1,2,4-triazol-3- yl)benzoyl)piperidin- 4-yl)-2-methylbenzonitrile

454 113 4-(1-(4-cyclobutyl-2- methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)benzoyl)piperidin- 4-yl)-2-fluorobenzonitrile

458 114 4-(1-(4-cyclobutyl-2- methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4- yl)-3-fluorobenzonitrile

458 115 2-chloro-4-(1-(4- cyclobutyl-2-methyl-5- (5-methyl-4H-1,2,4-triazol-3- yl)benzoyl)piperidin-4- yl)benzonitrile

474 117 4-(1-(4-cyclobutyl-2- methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)benzoyl)piperidin- 4-yl)-3- methylbenzonitrile

454 118 3-chloro-4-(1-(4- cyclobutyl-2-methyl-5- (5-methyl-4H-1,2,4-triazol-3- yl)benzoyl)piperidin-4- yl)benzonitrile

474 119 4-(1-(4-cyclobutyl-2- methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)benzoyl)piperidin- 4-yl)-3- methoxybenzonitrile

470 120 4-(1-(4-cyclobutyl-2- methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)benzoyl)piperidin- 4-yl)-2- methoxybenzonitrile

470 135 (4-(4- bromophenyl)piperidin- 1-yl)(4-cyclobutyl-2-methyl-5-(5-methyl- 4H-1,2,4-triazol-3- yl)phenyl)methanone

493 150 4-(1-(4-cyclobutyl-3- (5-methyl-4H-1,2,4- triazol-3-yl)benzoyl)azetidin-3- yl)benzonitrile

398

The compounds in TABLE 9 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 78, 79, 80 and 81.

TABLE 9 m/z (ES+) Cpd Name Structure (M + H)⁺ 1214-(1-(4-cyclobutyl-5-(5- (hydroxymethyl)-4H- 1,2,4-triazol-3-yl)-2-methylbenzoyl)-4- fluoropiperidin-4- yl)benzonitrile

474 123 5-(5-(4-(4- cyanophenyl)piperidine- 1-carbonyl)-2- cyclobutyl-4-methylphenyl)-4H- 1,2,4-triazole-3- carbonitrile

451 130 methyl 2-(5-(5-(4-(4- cyanophenyl)piperidine- 1-carbonyl)-2-cyclobutyl-4- methylphenyl)-4H- 1,2,4-triazol-3- yl)acetate

498 131 2-(5-(5-(4-(4- cyanophenyl)piperidine- 1-carbonyl)-2-cyclobutyl-4- methylphenyl)-4H- 1,2,4-triazol-3-yl)acetic acid

484

Compound 95.4-(1-(3-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound250, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1). m/z (ES+) 391 (M+H)⁺.

Compound 101.1. 4-Fluoro-5-iodo-2-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.3, except 4-fluoro-2-methylbenzoic acid was used in place of2,4-dimethylbenzoic acid.

Compound 101.2. Methyl 4-fluoro-5-iodo-2-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound6.1, except 4-fluoro-5-iodo-2-methylbenzoic acid (compound 101.1) wasused in place of 4-bromo-2-methylbenzoic acid.

Compound 101.3. Methyl 5-cyano-4-fluoro-2-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound6.4, except methyl 4-fluoro-5-iodo-2-methylbenzoate (compound 101.2) wasused in place of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound6.3).

Compound 101.4.4-(1-(4-Fluoro-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 78,except methyl 5-cyano-4-fluoro-2-methylbenzoate (compound 101.3) wasused in place of methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound6.4) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) wasused in place of 6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride(compound 78.5).

Compound 101.4-(1-(2-Methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)-4-(piperidin-1-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 25,except4-(1-(4-fluoro-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 101.4) was used in place of4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile(compound 25.1) and piperidine was used in place of azetidinehydrochloride. m/z (ES+) 469 (M+H)⁺.

The compounds in TABLE 10 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 101.

TABLE 10 m/z (ES+) Cpd Name Structure (M + H)⁺ 1024-(1-(2-methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)-4-morpholinobenzoyl)piperidin- 4-yl)benzonitrile

471 105 4-(1-(2-methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)-4-(3-methylpyrrolidin-1- yl)benzoyl)piperidin-4- yl)benzonitrile

469 109 4-(1-(4-(dimethylamino)-2- methyl-5-(5-methyl-4H-1,2,4-triazol-3- yl)benzoyl)piperidin-4- yl)benzonitrile

429 122 4-(1-(2-methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)-4-(4-methylpiperazin-1- yl)benzoyl)piperidin-4- yl)benzonitrile

484 124 (S)-4-(1-(2-methyl-5-(5- methyl-4H-1,2,4-triazol-3-yl)-4-(2-methylpyrrolidin-1- yl)benzoyl)piperidin-4- yl)benzonitrile

469 125 (S)-4-(1-(4-(3- methoxypyrrolidin-1-yl)-2-methyl-5-(5-methyl-4H-1,2,4- triazol-3- yl)benzoyl)piperidin-4-yl)benzonitrile

485 126 (R)-4-(1-(4-(3- methoxypyrrolidin-1-yl)-2-methyl-5-(5-methyl-4H-1,2,4- triazol-3- yl)benzoyl)piperidin-4-yl)benzonitrile

485 127 (R)-4-(1-(2-methyl-5-(5- methyl-4H-1,2,4-triazol-3-yl)-4-(2-methylpyrrolidin-1- yl)benzoyl)piperidin-4- yl)benzonitrile

469 128 4-(1-(2-methyl-5-(5-methyl- 4H-1,2,4-triazol-3-yl)-4-(3-methylazetidin-1- yl)benzoyl)piperidin-4- yl)benzonitrile

455 129 4-(1-(4-(diethylamino)-2- methyl-5-(5-methyl-4H-1,2,4-triazol-3- yl)benzoyl)piperidin-4- yl)benzonitrile

457

Compound 132.1. Methyl 4-fluoro-3-iodobenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound6.1, except 4-fluoro-3-iodobenzoic acid was used in place of4-bromo-2-methylbenzoic acid.

Compound 132.2. Methyl 3-(2-bromoacetyl)-4-fluorobenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound27.3, except methyl 4-fluoro-3-iodobenzoate (compound 132.1) was used inplace of methyl 3-(2-bromoacetyl)-4-methylbenzoate (compound 27.2).

Compound 132.3.4-(1-(4-Fluoro-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except methyl 3-(2-bromoacetyl)-4-fluorobenzoate (compound 132.1) wasused in place of methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate(compound 1.6).

Compound 132.4-(1-(4-(Azetidin-1-yl)-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 25,except4-(1-(4-fluoro-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 132.3) was used in place of4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile(compound 25.1). m/z (ES+) 426 (M+H)⁺.

Compound 139.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-methyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) wasused instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2). m/z (ES+) 382 (M+H)⁺.

Compound 151.1. 2-(Morpholin-4-yl)-5-nitropyridin-4-amine

Into a 50-mL sealed tube, were placed a solution of2-chloro-5-nitropyridin-4-amine (500 mg, 2.88 mmol) inN,N-dimethylformamide (20 mL) and morpholine (503 μL, 5.77 mmol). Thereaction mixture was stirred overnight at 55° C. The reaction was thenquenched by the addition of 100 mL of water. The reaction mixture wasextracted with 3×150 mL of ethyl acetate. The organic layers werecombined, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. This resulted in 733 mg (crude) of the title compoundas a yellow solid.

Compound 151.2. 6-Morpholinopyridine-3,4-diamine

Into a 50-mL round-bottom flask were placed2-(morpholin-4-yl)-5-nitropyridin-4-amine (compound 151.1, 350 mg, 1.56mmol), methanol (20 mL), THF (10 mL), and Pd/C (35 mg). The abovesolution was purged with N₂ and then H₂. The reaction mixture wasstirred for 4 h at room temperature. The solids were filtered out. Theresulting mixture was concentrated under reduced pressure. This resultedin 280 mg (92%) of the title compound as a pink solid.

Compound 151.3. 5-Formyl-2,4-dimethylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound4.1, except 5-iodo-2,4-dimethylbenzoic acid (compound 1.3) was used inplace of 3-bromo-4-methylbenzoic acid.

Compound 151.4.4-(1-(5-Formyl-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

Into a 50-mL round-bottom flask, was placed a solution of5-formyl-2,4-dimethylbenzoic acid (compound 151.3, 500 mg, 2.81 mmol) inDCM (10 mL). 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2,545 mg, 2.80 mmol), DIEA (1.4 mL, 8.41 mmol) and HBTU (1.60 g, 4.22mmol) were added. The reaction mixture was stirred for 3 h at roomtemperature. The reaction mixture was diluted with 150 mL of EtOAc, thenwashed with 2×50 mL of NH₄Cl (sat.) and 1×50 mL of brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1/1) as eluent to furnish 480 mg (54%) of thetitle compound as a white solid.

Compound 151.4-(1-(2,4-Dimethyl-5-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

Into a 50-mL round-bottom flask, was placed a solution of4-(1-(5-formyl-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile (compound151.4, 159 mg, 0.50 mmol) in ethanol (16 mL).6-Morpholinopyridine-3,4-diamine (compound 151.2, 194 mg, 1.00 mmol) andNH₄OAc (308 mg, 4.00 mmol) were added to the reaction. The reactionmixture was stirred for 3 days at 70° C. under air. The pH of thesolution was adjusted to 8-9 with sodium bicarbonate (sat.). Thereaction mixture was extracted with 1×100 mL of ethyl acetate. Theorganic layer was washed with 3×50 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct (200 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD Column, 5 m,19*150 mm; mobile phase, WATER WITH 0.05% TFA and CH₃CN (20.0% CH₃CN upto 36.0% in 10 min, up to 100.0% in 1 min, down to 20.0% in 2 min);Detector, UV 254 and 220 nm. This resulted in 94.1 mg (38%) of the titlecompound as a brown solid. m/z (ES+) 493 (M+H)⁺.

Compound 152.4-(1-(4-Methyl-3-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound151, except 3-formyl-4-methylbenzoic acid (compound 4.1) was used inplace of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3). m/z (ES+)479 (M+H)⁺.

Compound 153.1. 6-(Pyrrolidin-1-yl)pyridine-3,4-diamine

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound151.1 and 151.2, except pyrrolidine was used in place of morpholine.

Compound 153.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound151, except 6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 153.1) wasused in place of 6-morpholinopyridine-3,4-diamine (compound 151.2). m/z(ES+) 477 (M+H)⁺.

Compound 154.4-(1-(4-Methyl-3-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound151, except 3-formyl-4-methylbenzoic acid (compound 4.1) was used inplace of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3) and6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 153.1) was used inplace of 6-morpholinopyridine-3,4-diamine (compound 151.2). m/z (ES+)463 (M+H)⁺.

Compound 155.1. 6-(Azetidin-1-yl)pyridine-3,4-diamine

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound151.1 and 151.2, except azetidine was used in place of morpholine.

Compound 155.4-(1-(3-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound151, except 3-formyl-4-methylbenzoic acid (compound 4.1) was used inplace of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3) and6-(azetidin-1-yl)pyridine-3,4-diamine (compound 155.1) was used in placeof 6-morpholinopyridine-3,4-diamine (compound 151.2). m/z (ES+) 449(M+H)⁺.

Compound 156.1. 3-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound2.3, except 3-iodobenzoic acid was used in place of5-iodo-2,4-dimethylbenzoic acid (compound 1.3).

Compound 156.4-(1-(3-(2-(Methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except 3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoic acid(compound 156.1) was used in place of5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 2.3). m/z (ES+) 415 (M+H)⁺.

Compound 157.1. Methyl3-(2-(2-hydroxyethyl)-1H-imidazol-5-yl)-4-methylbenzoate

Into a 250-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was placed a solution of methyl3-(2-bromoacetyl)-4-methylbenzoate (compound 27.2, 10 g, 36.89 mmol) inN,N-dimethylformamide (150 mL). K₂CO₃ (30 g, 215.5 mmol) and3-hydroxypropanimidamide hydrochloride (compound 23.1, 15 g, 120.4 mmol)were added to the reaction. The reaction mixture was stirred for 12 h at80° C., then concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(2:1) as eluent to furnish 2 g (21%) of the title compound as a lightyellow oil.

Compound 157.2. Methyl3-(2-(2-(azetidin-1-yl)ethyl)-1H-imidazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds24.1 and 24, except methyl3-(2-(2-hydroxyethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound157.1) was used in place of4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 23) and azetidine was used in place of dimethylamine.

Compound 157.3.3-(2-(2-(Azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds27.4 and 27.5, except methyl3-(2-(2-(azetidin-1-yl)ethyl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 157.2) was used in place of methyl3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3).

Compound 157.4-(1-(3-(2-(2-(Azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 27,except3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 157.3) was used in place of3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 27.5) and 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2) was used in place of 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.2). m/z (ES+) 460 (M+H)⁺.

Compound 158.4-(1-(3-(2-(2-(Azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 27,except3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 157.3) was used in place of4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+)488 (M+H)⁺.

Compound 159.1. 2-Isopropyl-4-methyl-1H-imidazole

A solution of isobutyraldehyde (4.5 mL, 50 mmol) in ethanol (25 mL) wastreated with ammonium hydroxide (28% w/w, 25 mL) at 55° C. Methylglyoxal(40% in H₂O, 28 mL, 63 mmol) was added dropwise. The resulting mixturewas stirred at 60° C. for 16 hours and the solvent was removed underreduced pressure. The residue was partitioned between EtOAc (50 mL) andwater (30 mL). The organic phase was washed by brine, dried over MgSO₄and concentrated under reduced pressure. The residue was purified byflash chromatography (SiO₂; 0-4% MeOH in dichloromethane) to give 3.96 g(64%) of the title compound as a yellow solid. m/z (ES+) 125 (M+H)⁺.

Compound 159.2. 5-Iodo-2-isopropyl-4-methyl-1H-imidazole

2-Isopropyl-4-methyl-1H-imidazole (3.96 g, 32 mmol) andN-iodosuccinimide (8.33 g, 35 mmol) were dissolved in acetonitrile (100mL) and heated to reflux for 16 hours. The reaction was concentratedunder reduced pressure and the residue was partitioned between EtOAc (50mL) and water (50 mL). The organic phase was washed with brine, driedover MgSO₄ and concentrated under reduced pressure. The residue waspurified by flash chromatography (SiO₂; 0-40% EtOAc in hexane) to give4.87 g (61%) of the title compound as a yellow solid. m/z (ES+) 251(M+H)⁺.

Compound 160.1. Methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.4, except methyl 5-iodo-2,4-dimethylbenzoate (compound 31.1) was usedin place of methyl 3-iodo-4-methylbenzoate (compound 5.3). m/z (ES+) 291(M+H)⁺.

Compound 160.2. 2-Cyclopropyl-5-iodo-4-methyl-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159.2, except cyclopropanecarbaldehyde was used in place ofisobutyraldehyde.

Compound 160.3. Methyl5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) and 2-cyclopropyl-5-iodo-4-methyl-1H-imidazole (compound160.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound5.5). m/z (ES+) 285 (M+H)⁺.

Compound 160.4.5-(2-Cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 160.3) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 271 (M+H)⁺.

Compound 160.4-(1-(5-(2-Cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoicacid (compound 160.4) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 411 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.51 (br, 1H),7.85-7.80 (m, 2H), 7.62-7.56 (m, 2H), 7.20 and 7.13 (2 singlets, Ar—H,1H), 7.10 and 7.07 (2 singlets, Ar—H, 1H), 4.49-4.40 (m, 1H), 4.36-4.28(m, 1H), 4.06-3.88 (m, 3H), 2.33 and 2.30 (2 singlets, CH₃, 3H), 2.23and 2.18 (2 singlets, CH₃, 3H), 2.07 and 1.93 (2 singlets, amiderotamers, CH₃, 3H), 1.89-1.82 (m, 1H), 0.88-0.074 (m, 4H).

Compound 161.4-(1-(5-(2-Cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoicacid (compound 160.4) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 429 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.52(br, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (dd, J=8.4 Hz, 3.2 Hz, 2H), 7.21(d, J=6.8 Hz, 1H), 7.13 (s, 1H), 4.56-4.34 (m, 4H), 2.35 and 2.32 (2singlets, CH₃, 3H), 2.43 and 2.18 (2 singlets, CH₃, 3H), 2.07 and 1.93(2 singlets, CH₃, 3H), 1.90-1.80 (m, 1H), 0.88-0.74 (m, 4H).

Compound 159.3.5-(2-Isopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except 5-iodo-2-isopropyl-4-methyl-1H-imidazole (compound 159.2)was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) andmethyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4).

Compound 159.4-(1-(5-(2-Isopropyl-5-methyl-1H-imidazol-4-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The mixture of 5-(2-isopropyl-5-methyl-1H-imidazol-4-yl)-2,4-dimethylbenzoic acid (compound 159.3, 250 mg, 0.92 mmol),4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 195 mg, 1.0mmol), EDCI (264 mg, 1.4 mmol), HOBt (170 mg, 1.0 mmol) and DIEA (640μL, 3.7 mmol) in DMF (10 mL) was stirred at room temperature for 16hours. The reaction was diluted with saturated NaHCO₃ and extracted withEtOAc (60 mL). The organic phase was washed with brine (3×20 mL), driedover MgSO₄ and concentrated under reduced pressure. The residue waspurified by preparative TLC with 8% methanol in dichloromethane andlyophilized to give 85 mg (22%) of the title compound as a white solid.m/z (ES+) 413 (M+H)⁺.

Compound 162.4-(1-(3-(2-Isopropyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1). m/z (ES+) 399 (M+H)⁺.

Compound 163.4-(1-(3-(2-Isopropyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159, except 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2) and methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1). m/z (ES+) 427 (M+H)⁺.

Compound 164.1.5-Iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159.2, except tetrahydro-2H-pyran-4-carbaldehyde was used in place ofisobutyraldehyde.

Compound 164.2.2,4-Dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except 5-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole(compound 164.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4).

Compound 164.4-(1-(2,4-Dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The mixture of2,4-dimethyl-5-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)benzoicacid (compound 164.2, 157 mg, 0.5 mmol), 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2, 126 mg, 0.65 mmol), EDCI (143 mg, 0.75mmol), HOBt (93 mg, 0.55 mmol) and DIEA (345 μL, 2.00 mmol) in DMF (4mL) was stirred at room temperature for 16 hours. The reaction wasdiluted with water and extracted with EtOAc (30 mL). The organic phasewas washed with saturated NaHCO₃ (10 mL), brine (3×20 mL), dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby preparative TLC with 5% methanol in dichloromethane and lyophilizedto give 95 mg (42%) of the title compound as a white solid. m/z (ES+)455 (M+H)⁺.

Compound 165.4-(1-(2,4-Dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound164, except 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 483 (M+H)⁺.

Compound 166.4-(4-Fluoro-1-(4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound164, except 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride(compound 13.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 501 (M+H)⁺.

Compound 167.4-(1-(2,4-Dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound164, except 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 459 (M+H)⁺.

Compound 168.1.4-Methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except 5-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole(compound 164.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5).

Compound 168.4-(1-(4-Methyl-3-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound164, except4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid (compound 168.1) was used in place of2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid (compound 164.2). m/z (ES+) 441 (M+H)⁺.

Compound 169.4-(1-(4-Methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound164, except4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid (compound 168.1) was used in place of2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid (compound 164.2) and 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2) m/z (ES+) 469 (M+H)⁺.

Compound 170.4-(3-Fluoro-1-(4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoyl) azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound164, except4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid (compound 168.1) was used in place of2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoicacid (compound 164.2) and 4-(3-fluoroazetidin-3-yl)benzonitrilehydrochloride (compound 43.4) was used in place of4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+)459 (M+H)⁺.

Compound 171.1. 5-Iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159.2, except tetrahydrofuran-3-carbaldehyde was used in place ofisobutyraldehyde.

Compound 171.2.2,4-Dimethyl-5-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole(compound 171.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4).

Compound 171.4-(1-(2,4-Dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile

The mixture of2,4-dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)benzoicacid (compound 171.2, 100 mg, 0.30 mmol), 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2, 71 mg, 0.37 mmol), EDCI (95 mg, 0.50 mmol),HOBt (20 mg, 0.10 mmol) and DIEA (207 μL, 1.20 mmol) in DMF (5 mL) wasstirred at room temperature for 16 hours. The reaction was concentratedunder reduced pressure, diluted with saturated NaHCO₃ (10 mL) andextracted with EtOAc (30 mL). The organic phase was washed with brine(3×10 mL), dried over MgSO₄ and concentrated under reduce pressure. Theresidue was purified by preparative TLC with 6% methanol indichloromethane and lyophilized to give 16 mg (12%) of the titlecompound as a white solid. m/z (ES+) 441 (M+H)⁺.

Compound 172.1.4-Methyl-3-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole(compound 171.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5).

Compound 172.4-(1-(4-Methyl-3-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound171, except4-methyl-3-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 172.1) was used in place of2,4-dimethyl-5-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 171.2). m/z (ES+) 427 (M+H)⁺.

Compound 173.1. 5-Iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159.2, except tetrahydrofuran-2-carbaldehyde was used in place ofisobutyraldehyde. m/z (ES+) 279 (M+H)⁺.

Compound 173.2.2,4-Dimethyl-5-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole(compound 173.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4).

Compound 173.4-(1-(2,4-Dimethyl-5-(5-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound171, except2,4-dimethyl-5-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoicacid (compound 173.2) was used in place of2,4-dimethyl-5-(4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 171.2). m/z (ES+) 441 (M+H)⁺.

Compound 174.1.4-Methyl-3-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole(compound 173.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5).

Compound 174.4-(1-(4-Methyl-3-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound171, except4-methyl-3-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazol-5-yl)benzoicacid (compound 174.1) was used in place of2,4-dimethyl-5-(4-methyl-2(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 171.2). m/z (ES+) 427 (M+H)⁺.

Compound 175.1. 4-Methyl-2-(3-methyloxetan-3-yl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound16.2, except 3-methyloxetane-3-carbaldehyde was used in place ofacetaldehyde and 2-oxopropanal was used in place of3,3,3-trifluoro-2-oxopropanal (compound 16.1). m/z (ES+) 153 (M+H)⁺.

Compound 175.2. 5-Iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole

NIS (2.61 g, 11.58 mmol) was added portion-wise to a solution of4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1, 1.76 g,11.58 mmol) in acetonitrile (60 mL). The mixture was stirred at roomtemperature for 1 hour, then was partitioned between EtOAc (300 mL) andwater (80 mL). The organic layer was washed with saturated sodiumthiosulfate (50 mL), brine (50 mL), dried (MgSO₄) and concentrated underreduced pressure to give the title compound as a light yellow solid (3.0g, 93%). m/z (ES+) 279 (M+H)⁺.

Compound 175.3. Methyl2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) and 5-iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole(compound 175.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5). m/z (ES+) 315 (M+H)⁺.

Compound 175.4.2,4-Dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate(compound 175.3) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 301 (M+H)⁺.

Compound 175.4-(1-(2,4-Dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 175.4) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 441 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.72 (br, 1H), 7.83(d, J=8.4 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.21 and 7.18 (2 singlets,Ar—H, 1H), 7.13 (s, 1H), 4.90 (d, J=4.8 Hz, 2H), 4.5-4.43 (m, 1H), 4.12(d, J=5.6 Hz, 2H), 4.36-4.28 (m, 1H), 4.07-3.90 (m, 3H), 2.32 (s, 3H),2.28 and 2.18 (2 singlets, CH₃, 3H), 2.13 and 2.00 (2 singlets, CH₃,3H), 1.67 (s, 3H).

Compound 176.4-(1-(2,4-Dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 175.4) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 459 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.73(br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.25 and 7.24(2 singlets, Ar—H, 1H), 7.19 and 7.16 (2 singlets, Ar—H, 1H), 4.94-4.86(m, 2H), 4.57-4.35 (m, 6H), 2.36 and 2.34 (2 singlets, CH₃, 3H), 2.29and 2.19 (2 singlets, CH₃, 3H), 2.14 and 2.00 (2 singlets, CH₃, 3H),1.67 (s, 3H).

Compound 177.1. Methyl4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except 5-iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole(compound 175.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5). m/z (ES+) 301 (M+H)⁺.

Compound 177.2.4-Methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate(compound 177.1) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 287 (M+H)⁺.

Compound 177.4-(1-(4-Methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 177.2) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 427 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.79 (br, 1H), 7.84(d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.60-7.46 (m, 2H), 7.42-7.28(m, 1H), 4.91 (d, J=5.2 Hz, 2H), 4.76-4.67 (m, 1H), 4.52-4.36 (m, 4H),4.09-3.97 (m, 2H), 2.34 and 2.24 (2 singlets, CH₃, 3H), 2.16 and 2.02 (2singlets, CH₃, 3H), 1.68 (s, 3H).

Compound 178.4-(3-Fluoro-1-(4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 177.2) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 445 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.80(br, 1H), 7.96 (dd, J=8.0 Hz, 2.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H),7.67-7.52 (m, 2H), 7.44-7.33 (m, 1H), 4.95-4.89 (m, 2H), 4.89-4.46 (m,4H), 4.46-4.40 (m, 2H), 3.36 and 2.26 (2 singlets, CH₃, 3H), 2.17 and2.03 (2 singlets, CH₃, 3H), 1.69 and 1.68 (2 singlets, CH₃, 3H).

Compound 179.4-(1-(4-Methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 177.2) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was usedin place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2).m/z (ES+) 455 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.78 (br, 1H), 7.78(d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.40-7.23 (m, 3H), 4.92 (t,J=6.0 Hz, 5.2 Hz, 2H), 4.78-4.52 (m, 1H), 4.43 (t, J=5.2 Hz, 4.8 Hz,2H), 3.91-3.71 (m, 1H), 3.24-3.08 (m, 1H), 2.98-2.88 (m, 2H), 2.34 and2.25 (2 singlets, CH₃, 3H), 2.16 and 2.03 (2 singlets, amide rotamers,CH₃, 3H), 1.91-1.59 (m, 4H), 1.69 and 1.68 (2 singlets, CH₃, 3H).

Compound 180.1. 4-Methyl-2-(oxetan-3-yl)-1H-imidazole

Dess-Martin reagent (4.33 g, 10.21 mmol) was added to a solution ofoxetan-3-ylmethanol (0.9 g, 10.21 mmol) in CH₂Cl₂ (10 mL) at 0° C. Themixture was stirred at 0° C. for 30 minutes and at room temperature for2 hours. CH₂Cl₂ was then removed under reduced pressure. The residue wasdissolved in EtOH (10 mL). NH₄OH (5 mL) was added, followed by2-oxopropanal (40% in water, 2.76 mL, 15.32 mmol). The mixture wasstirred at room temperature for 4 hours. Water (10 mL) was added to themixture and the mixture was lyophilized. The dried residue was purifiedwith column chromatography (2.5% MeOH to 5% MeOH in CH₂Cl₂) to give thetitle product as a brown oil (0.61 g, 43.3% for two steps). m/z (ES+)139 (M+H)⁺.

Compound 180.2. 5-Iodo-4-methyl-2-(oxetan-3-yl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound175.2, except 4-methyl-2-(oxetan-3-yl)-1H-imidazole (compound 180.1) wasused in place of 4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound175.1). m/z (ES+) 265 (M+H)⁺.

Compound 180.3. Methyl2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) and 5-iodo-4-methyl-2-(oxetan-3-yl)-1H-imidazole(compound 180.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5). m/z (ES+) 301 (M+H)⁺.

Compound 180.4.2,4-Dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoate(compound 180.3) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 287 (M+H)⁺.

Compound 180.4-(1-(2,4-Dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 180.4) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 427 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.81 (br, 1H), 7.84(d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.26-7.10 (m, 2H), 4.87-4.75(m, 4H), 4.51-4.42 (m, 1H), 4.37-4.21 (m, 2H), 4.07-3.91 (m, 3H), 2.33(s, 3H), 2.27 and 2.19 (2 singlets, CH₃, 3H), 2.12 and 2.02 (2 singlets,CH₃, 3H).

Compound 181.4-(1-(2,4-Dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoicacid (compound 180.4) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 445 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.80(br, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.24 (s, 1H),7.18 (d, J=7.2 Hz, 2H), 4.87-4.75 (m, 4H), 4.60-4.36 (m, 4H), 4.31-4.21(m, 1H), 2.35 (s, CH3, 3H), 2.90 and 2.20 (2 singlets, CH₃, 3H), 2.13and 2.02 (2 singlets, CH₃, 3H).

Compound 182.1. tert-Butyl4-(5-iodo-4-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159.2, except tert-butyl 4-formylpiperidine-1-carboxylate was used inplace of isobutyraldehyde. m/z (ES+) 392 (M+H)⁺.

Compound 182.2.3-(2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except tert-butyl4-(5-iodo-4-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound182.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound5.5).

Compound 182.3. tert-Butyl4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate

A mixture of3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 182.2, 506 mg), 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2, 296 mg, 1.52 mmol), EDCI (315 mg, 1.65mmol), HOBt (107 mg, 0.64 mmol) and DIEA (877 μL, 5.08 mmol) in DMF (25mL) was stirred at room temperature for 16 hours. The reaction wasconcentrated under reduced pressure, diluted with saturated NaHCO₃ (20mL) and extracted with EtOAc (50 mL). The organic phase was washed withbrine (3×10 mL), dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by preparative TLC with 8% methanolin dichloromethane to give 476 mg (69%) of the title compound as a foam.m/z (ES+) 540 (M+H)⁺.

Compound 182.4-(1-(4-Methyl-3-(4-methyl-2-(1-methylpiperidin-4-yl)-1H-imidazol-5-yl)benzoyl) azetidin-3-yl)benzonitrile

To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate(compound 182.3, 475 mg, 0.88 mmol) in 20 mL CH₂Cl₂, was addedtrifluoroacetic acid (4 mL). The reaction stirred for 1.5 hours andconcentrated under reduced pressure, neutralized with 10 mL Na₂CO₃ (1M)and lyophilized to afford4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile.The mixture of4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (135 mg, 0.31 mmol), formic acid (300μL, 6.76 mmol), formaldehyde (37% in water, 300 μL, 3.41 mmol) and water(1.5 mL) was heated to reflux for 10 hours. The reaction was dilutedwith saturated NaHCO₃ until pH 9 and extracted with CH₂Cl₂ (3×20 mL).The residue was purified by preparative TLC with 10% methanol and 1%ammonium hydroxide in dichloromethane and lyophilized to give 43 mg (30%two steps) of the title compound as a white solid. m/z (ES+) 540 (M+H)⁺.

Compound 183.4-(1-(3-(2-(1-Acetylpiperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

To a solution of tert-butyl4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate(compound 182.3, 475 mg, 0.88 mmol) in 20 mL DCM, was addedtrifluoroacetic acid (4 mL). The reaction was stirred for 1.5 hours,concentrated under reduced pressure and neutralized with 10 mL Na₂CO₃(1M) to obtain a crude product after lyophilization. A mixture of4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile(252 mg, 0.57 mmol), acetic anhydride (71 μL, 0.75 mmol) andtriethylamine (120 μL, 0.86 mmol) was stirred at room temperature for 16hours. The reaction was concentrated under reduced pressure, thendiluted with saturated NaH₂PO₄ (20 mL) and extracted with EtOAc (3×20mL). The organic phase was dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by preparative TLC with 10%methanol in dichloromethane and lyophilized to give 235 mg (80%-2 steps)of the title compound as a white solid. m/z (ES+) 482 (M+H)⁺.

Compound 184. Methyl 4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 227 mg, 0.42 mmol) in CH₂Cl₂(10 mL), was added trifluoroacetic acid (2 ml). The reaction was stirredfor 1.5 hours and concentrated under reduced pressure. The reactionmixture was neutralized with 2 mL Na₂CO₃ (1M) to afford the crudeintermediate after lyophilization. A mixture of4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile(185 mg, 0.42 mmol) and diisopropyl ethylamine (363 μL, 2.1 mmol) weredissolved in DMF (6 mL). Methyl chloroformate (36 μL, 0.46 mmol) wasadded and the mixture was stirred at room temperature for 1 hour. Thereaction was concentrated, diluted with saturated NaH₂PO₄ (20 mL) andextracted with EtOAc (3×20 ml). The organic phase was washed by brine,dried over MgSO₄ and concentrated under reduced pressure. The residuewas purified by preparative TLC with 10% methanol in dichloromethane andlyophilized to give 141 mg (67%, over 2 steps) of the title compound asa white solid. m/z (ES+) 498 (M+H)⁺.

Compound 185.1. tert-Butyl4-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159.2, except tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate wasused in place of isobutyraldehyde. m/z (ES+) 406 (M+H)⁺.

Compound 185.2.3-(2-(1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except tert-butyl4-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate(compound 185.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5).

Compound 185.3. tert-Butyl4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound182.3, except3-(2-(1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 185.2) was used in place of3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 182.2).

Compound 185. Methyl 4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound184, except tert-butyl4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate(compound 185.3) was used in place of tert-butyl4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3). m/z (ES+) 512 M+H+.

Compound 186. Methyl4-(5-(5-(3-(4-cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound184, except tert-butyl4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate(compound 185.3) was used in place of tert-butyl4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate(compound 182.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 530 (M+H)⁺.

Compound 187.4-(1-(4-Methyl-3-(4-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159, except 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde was used in placeof isobutyraldehyde and methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1). m/z (ES+) 455 (M+H)⁺.

Compound 188.1. Ethyl 4-methyltetrahydro-2H-pyran-4-carboxylate

Into a 500-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof ethyl tetrahydro-2H-pyran-4-carboxylate (8 g, 50.6 mmol) intetrahydrofuran (100 mL). This was followed by the addition of LDA (50mL, 101.1 mmol, 2M in THF) dropwise at −78° C. and stirred for 3 h. Tothis was added a solution of CH₃I (9.5 mL, 151.9 mmol) intetrahydrofuran (50 mL) dropwise at −78° C. The reaction mixture wasstirred for 3 h at −78° C., then carefully quenched with 400 mL of NH₄Cl(sat.). The aqueous phase was extracted with 300 mL of ethyl acetate andthe combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. This resulted in 8 g (92%) of thetitle compound as a yellow oil.

Compound 188.2. (4-Methyltetrahydro-2H-pyran-4-yl)methanol

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof ethyl 4-methyltetrahydro-2H-pyran-4-carboxylate (compound 188.1, 500mg, 2.90 mmol) in tetrahydrofuran (12 mL). This was followed by theaddition of lithium aluminum hydride (221 mg, 5.82 mmol) in portions at0° C. The reaction mixture was stirred for 1 h at room temperature, thencarefully quenched with 1.2 mL of H₂O, 1.2 mL of NaOH (15%), 3.5 mL ofH₂O. The solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. This resulted in 300 mg (crude) ofthe title compound as a yellow oil.

Compound 188.3. 4-Methyltetrahydro-2H-pyran-4-carbaldehyde

Into a 100-mL 3-neck round-bottom flask, was placed a solution of(4-methyltetrahydro-2H-pyran-4-yl)methanol (compound 188.2, 300 mg, 2.30mmol) in dichloromethane (15 mL). Dess-Martin reagent (1.17 g, 2.76mmol) was added to the reaction. The reaction mixture was stirred for 2h at room temperature, then quenched with 15 mL of water. The aqueousphase was extracted with 20 mL of dichloromethane. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. This resulted in 200 mg (68%) of the title compound asa yellow oil.

Compound 188.4-(1-(4-Methyl-3-(4-methyl-2-(4-methyltetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159, except 4-methyltetrahydro-2H-pyran-4-carbaldehyde (compound 188.3)was used in place of isobutyraldehyde and methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1). m/z (ES+) 455 (M+H)⁺.

Compound 189.1. tert-Butyl3-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)azetidine-1-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound182.3, except tert-butyl 3-formylazetidine-1-carboxylate was used inplace of tert-butyl 4-formylpiperidine-1-carboxylate.

Compound 189.2.4-(1-(3-(2-(Azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl3-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)azetidine-1-carboxylate(compound 189.1, 2 g, 3.91 mmol) in 1,4-dioxane (20 mL). Hydrogenchloride (4 M) (10 mL) was added to the reaction. The reaction mixturewas stirred for 2 h at 30° C., then concentrated under reduced pressure.The pH of the solution was adjusted to 7-8 with sodium bicarbonate(sat.). The resulting mixture was concentrated under reduced pressure togive 800 mg (crude) of the title compound as a white solid.

Compound 189.4-(1-(3-(2-(1-Acetylazetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 25-mL round-bottom flask, was placed a solution of4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 189.2, 80 mg, 0.19 mmol) in N,N-dimethylformamide (1 mL).Triethylamine (27 μL, 0.20 mmol) and acetic anhydride (19 μL, 0.20 mmol)were added to the reaction. The reaction mixture was stirred for 2 h atroom temperature, then quenched with 10 mL of water. The aqueous phasewas extracted with 3×3 mL of ethyl acetate and the combined organicextracts were concentrated under reduced pressure. The crude product(100 mg) was purified by Prep-HPLC with the following conditions(Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 m, 19*150 mm;mobile phase, Water with 50 mmol NH₄HCO₃ and MeCN (28% MeCN up to 40% in7 min, up to 100% in 2 min, down to 28% in 1 min); Detector, Waters 2489255 and 220 nm. This resulted in 32.8 mg (37%) of the title compound asa white solid. m/z (ES+) 454 (M+H)⁺.

Compound 190. Methyl3-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)azetidine-1-carboxylate

Into a 25-mL round-bottom flask, was placed a solution of4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 189.2, 100 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL).Methyl chloroformate (33 μL, 0.42 mmol) and triethylamine (34 μL, 0.25mmol) were added to the reaction. The reaction mixture was stirred for 2h at room temperature, then was quenched with 10 mL of water. Theaqueous phase was extracted with 3×5 mL of ethyl acetate. The combinedorganic layers were washed with 3×3 mL of brine and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith dichloromethane/methanol (10:1). The crude product (100 mg) waspurified by Prep-HPLC with the following conditions (Prep-HPLC-020):Column, SunFire Prep C18 OBD Column, 5 m, 19*150 mm; mobile phase, Waterwith 50 mmol NH₄HCO₃ and MeCN (33.0% MeCN up to 45.0% in 7 min, up to100.0% in 2 min, down to 33.0% in 1 min); Detector, Waters 2489, 254 and220 nm. This resulted in 21.5 mg (19%) of the title compound as a whitesolid. m/z (ES+) 470 (M+H)⁺.

Compound 191.4-(1-(4-Methyl-3-(4-methyl-2-(1-methylazetidin-3-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

Into a 50-mL round-bottom flask, was placed a solution of4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 189.2, 50 mg, 0.12 mmol) in tetrahydrofuran (1 mL).Formaldehyde (65 μL, 37% wt, 0.57 mmol) and NaBH₃CN (30 mg, 0.48 mmol)were added to the reaction. The reaction mixture was stirred for 1 h atroom temperature. The reaction mixture was extracted with 3×3 mL ofethyl acetate and the combined organic extracts were washed with 3×1 mLof brine and concentrated under reduced pressure. The crude product (20mg) was purified by Prep-HPLC with the following conditions(Prep-HPLC-020): Column, XBridge Prep C18 OBD Column, 5 μm, 19*150 mm;mobile phase, WATER WITH 0.03% NH₃H₂O and MeCN (26.0% MeCN up to 40.0%in 7 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector,Waters 2489, 254 and 220 nm. This resulted in 1.8 mg (3%) of the titlecompound as a white solid. m/z (ES+) 426 (M+H)⁺.

Compound 192.1.4-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

Into a 1-L three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 4-methyl-1H-imidazole (10 g, 121.8 mmol) in tetrahydrofuran (200 mL).This was followed by the addition of sodium hydride (7.32 g, 182.7 mmol,60%) in several batches at 0° C. and stirred for 1 h at roomtemperature. To this was added SEM-Cl (30.5 g, 199.7 mmol) at 0° C. Themixture was stirred for 1 h at room temperature, then carefully quenchedwith 50 mL of brine. The aqueous phase was extracted with 1×800 mL ofethyl acetate. The organic layer was washed with 1×300 mL of brine,2×300 mL of sodium bicarbonate (sat.), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:1) ethyl acetate as eluent to furnish 9 g (35%) of the title compoundas a yellow oil.

Compound 192.2.3-(4-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol

Into a 1000-mL three-neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound192.1, 9 g, 42.38 mmol) in tetrahydrofuran (200 mL). This was followedby the addition of n-BuLi (34 mL, 2.5 M in THF) dropwise at −78° C. andstirred for 1 h. To this was added a solution of oxetan-3-one (6.11 g,84.79 mmol) in tetrahydrofuran (30 mL) dropwise at −78° C. The reactionmixture was stirred for 1 h at −78° C., then quenched with 50 mL ofNH₄Cl (sat.). The aqueous phase was extracted with 1×600 mL of ethylacetate. The organic layer was washed with 3×300 mL of brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thisresulted in 13 g (crude) of the title compound as a light yellow solid.

Compound 192.3.3-(5-Iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol

Into a 100-mL round-bottom flask, was placed a solution of3-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol(compound 192.2, 200 mg, 0.70 mmol) in ACN (10 mL). NIS (237.7 mg, 1.06mmol) was added to the reaction. The reaction mixture was stirredovernight at room temperature, then concentrated under reduced pressure.The reaction mixture was diluted with 40 mL of EtOAc. The organic layerwas washed with 3×20 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel chromatography with ethyl acetate/petroleum ether (2:3) aseluent to furnish 100 mg (35%) of the title compound as an orange oil.

Compound 192.4. Methyl3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-4-methylbenzoate

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof methyl 4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4, 282.7 mg, 1.02 mmol) in dioxane (12 mL). A solution ofK₃PO₄ (904.9 mg, 4.26 mmol) in water (1.2 mL),3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol(compound 192.3, 350 mg, 0.85 mmol) and Pd(dppf)₂Cl₂ (62.4 mg, 0.09mmol) were added to the reaction. The mixture was stirred for 7 h. Thereaction mixture was cooled, then diluted with 60 mL of EtOAc. Thesolids were removed by filtration, the filtrate was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(2:3) eluent to furnish 220 mg (60%) of the title compound as an orangeoil.

Compound 192.5. Methyl3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate

Into a 100-mL round-bottom flask, was placed methyl3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 192.4, 180 mg, 0.42 mmol), Et₃SiH (1 mL) and trifluoroaceticacid (2 mL). The reaction mixture was stirred for 4 h at roomtemperature. The pH of the solution was adjusted to 8 with sodiumhydroxide (1 M). The reaction mixture was diluted with 100 mL of brine.The aqueous phase was extracted with 2×30 mL of ethyl acetate, thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. This resulted in 150 mg (crude) ofthe title compound as an orange oil.

Compound 192.4-(1-(3-(2-(3-Hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except methyl3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate(compound 192.5) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 429 (M+H)⁺.

Compound 193.4-(1-(3-(2-(3-Fluorooxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 50-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof4-(1-(3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 192, 200 mg, 0.47 mmol) in dichloromethane (5 mL). This wasfollowed by the addition of a solution of DAST (76.2 μL, 0.58 mmol) indichloromethane (1 mL) dropwise at −78° C. The resulting solution wasstirred for 1 h at room temperature, then quenched by the addition of 2mL of sodium bicarbonate (sat.). The resulting solution was diluted with60 mL of EtOAc and additional water. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography with ethyl acetate aseluent. The crude product (50 mg) was purified by Prep-HPLC with thefollowing conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBDColumn, 5 m, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and MeCN(18.0% MeCN up to 28.0% in 9 min, up to 100.0% in 2 min, down to 18.0%in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 15.1mg (8%) of the title compound as a white solid. m/z (ES+) 431 (M+H)⁺.

Compound 194.1.5-Iodo-2-(3-methoxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

Into a 100-mL round-bottom flask, was placed a solution of3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol(compound 192.3, 800 mg, 1.95 mmol) in tetrahydrofuran (30 mL). This wasfollowed by the addition of sodium hydride (156.2 mg, 3.9 mmol, 60%) at0° C. and stirred for 20 min at room temperature. To this was added CH₃I(554.1 mg, 3.90 mmol) at 0° C. The resulting solution was stirred for 5h at room temperature, then quenched with 30 mL of Na₂S₂O₃ (sat.). Theaqueous phase was extracted with 3×40 mL of ethyl acetate, the combinedorganic layers were washed with 3×40 mL of brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:2) eluent to furnish 700 mg (85%) of the title compound as colorlessoil.

Compound 194.4-(1-(3-(2-(3-Methoxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound192, except5-iodo-2-(3-methoxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(compound 194.1) was used in place of3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol(compound 192.3). m/z (ES+) 443 (M+H)⁺.

Compound 195.4-(1-(3-(2-(4-Hydroxytetrahydro-2H-pyran-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound192, except dihydro-2H-pyran-4(3H)-one was used in place ofoxetan-3-one. m/z (ES+) 457 (M+H)⁺.

Compound 196.4-(1-(3-(2-(4-Methoxytetrahydro-2H-pyran-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound194, except dihydro-2H-pyran-4(3H)-one was used in place ofoxetan-3-one. m/z (ES+) 471 (M+H).

Compound 197.1. Pyrrolidine-1-carboximidamide hydrochloride

Into a 100-mL round-bottom flask, was placed a solution of pyrrolidine(5.8 mL, 70.30 mmol) in CH₃CN (30 mL). Triethylamine (9.8 mL, 70.17mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (10.2 g, 69.59mmol) was added to the reaction. The reaction mixture was stirredovernight at 60° C. The product was collected by filtration to yield 7.5g (71%) of the title compound as a white solid.

Compound 197.2. Methyl 3-(2-bromopropanoyl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound1.6, except 4-methylbenzoic acid was used in place of2,4-dimethylbenzoic acid.

Compound 197.3. Methyl4-methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoate

Into a 50-mL round-bottom flask, which was purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl3-(2-bromopropanoyl)-4-methylbenzoate (compound 197.2, 500.0 mg, 1.75mmol) in N,N-dimethylformamide (15 mL). Pyrrolidine-1-carboximidamidehydrochloride (compound 197.1, 260.8 mg, 1.75 mmol) was treated withK₂CO₃, then added to the reaction. The reaction mixture was stirred for1 h at 50° C. The reaction mixture was diluted with 30 mL of H₂O. Theaqueous phase was extracted with 3×30 mL of ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gelchromatography with PE/EtOAc (1:1)˜EtOAc/methanol (15:1) as eluent tofurnish 230.0 mg (44%) of the title compound as a dark blue solid.

Compound 197.4-(1-(4-Methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1,except methyl4-methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoate(compound 197.3) was used in place of methyl5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 1.7)and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was usedin place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2).m/z (ES+) 426 (M+H)⁺.

Compound 198.1. 1-(4-Methyl-1H-imidazol-2-yl)ethanone

Into a 500-mL round-bottom flask, was placed an aqueous solution of2-oxopropanal (25.2 mL, 222.0 mmol, 50%). Ammonium acetate (85 g, 1.10mol) and acetic acid (200 mL) were added to the reaction. The reactionmixture was stirred overnight at 100° C., then concentrated underreduced pressure. The residue was diluted with 300 mL of EtOAc. Theorganic layer was washed with 4×30 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by a silica gel chromatography with ethyl acetate/hexane (1:1)as eluent to furnish 1.5 g (11%) of the title compound as a yellowsolid.

Compound 198.2. Methyl5-(2-acetyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) and 1-(4-,ethyl-1H-imidazol-2-yl)ethanone (compound198.1) was used in place of 2,4-dimethyl-1H-imidazole.

Compound 198.3. Methyl5-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl5-(2-acetyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound198.2, 300 mg, 1.10 mmol) in methanol (30 mL). This was followed by theaddition of NaBH₄ (84 mg, 2.22 mmol) in portions at 0° C. The resultingsolution was stirred for 1 h at room temperature, then carefullyquenched with 1 mL of aqueous hydrogen chloride (2 M). The resultingmixture was concentrated under reduced pressure. This resulted in 330 mg(crude) of the title compound as a white solid.

Compound 198.4-(1-(5-(2-(1-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except methyl5-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 198.3) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 415 (M+H)⁺.

Compound 199.4-(3-Fluoro-1-(5-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound198, except 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 433 (M+H)⁺.

Compound 200.1. Methyl3-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound198.3, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1).

Compound 200.4-(1-(3-(2-(1-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound198, except methyl3-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate(compound 200.1) was used in place of methyl5-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 198.3). m/z (ES+) 401 (M+H)⁺.

Compound 201.4-(3-Fluoro-1-(3-(2-(1-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound200, except 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 419 (M+H)⁺.

Compound 202.1. 2-(3-Methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound16.2, except 3-methyloxetane-3-carbaldehyde was used in place ofacetaldehyde. m/z (ES+) 207 (M+H)⁺.

Compound 202.2.5-Iodo-2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound175.2, except 2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole(compound 202.1) was used in place of4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1). m/z(ES+) 333 (M+H)⁺.

Compound 202.3.5-Iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound16.3, except5-iodo-2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole(compound 202.2) was used in place of2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2). m/z (ES+) 290(M+H)⁺.

Compound 202.4. Methyl3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile(compound 202.3) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5). m/z (ES+) 312 (M+H)⁺.

Compound 202.5.3-(4-Cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 202.4) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 298 (M+H)⁺.

Compound 202.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 202.5) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 438 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 13.13 (br, 1H), 7.85(d, J=8.4 Hz, 2H), 7.73-7.66 (m, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.47 (d,J=8.0 Hz, 1H), 4.95 (d, J=5.6 Hz, 2H), 4.78-4.70 (m, 1H), 4.57-4.45 (m,2H), 4.46 (d, J=5.6 Hz, 2H), 4.11-4.01 (m, 2H), 2.39 (s, 3H), 1.71 (s,3H).

Compound 203.1. Methyl5-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) and5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound202.3) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound5.5). m/z (ES+) 326 (M+H)⁺.

Compound 203.2.5-(4-Cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-2,4-dimethylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.7, except methyl5-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 203.1) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 312 (M+H)⁺.

Compound 203.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except5-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-2,4-dimethylbenzoicacid (compound 203.2) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 452 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 13.01 (br, 1H), 7.84(d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.38 (s, 1H), 7.24 (s, 1H),4.94 (d, J=5.2 Hz, 2H), 4.53-4.32 (m, 4H), 4.09-3.96 (m, 3H), 2.36 (s,3H), 2.35 (s, 3H), 1.68 (s, 3H).

Compound 204.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except cyclopropanecarbaldehyde was used in place of acetaldehyde and4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used inplace of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2).m/z (ES+) 408 (M+H)⁺.

Compound 205.5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except cyclopropanecarbaldehyde was used in place of acetaldehyde. m/z(ES+) 436 (M+H)⁺.

Compound 206.5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except cyclopropanecarbaldehyde was used in place of acetaldehyde and4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 440 (M+H)⁺.

Compound 207.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-cyclopropyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except cyclopropanecarbaldehyde was used in place of acetaldehyde,4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used inplace of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) andmethyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 422 (M+H)⁺.

Compound 208.5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-methyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound43.4) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 414 (M+H)⁺.

Compound 209.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-methyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 396 (M+H)⁺.

Compound 210.5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-isopropyl-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound43.4) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2), methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, andisobutyraldehyde was used in place of acetaldehyde. m/z (ES+) 442(M+H)⁺.

Compound 211.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2) and tetrahydro-2H-pyran-4-carbaldehyde was used in place ofacetaldehyde. m/z (ES+) 452 (M+H)⁺.

Compound 212.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2), tetrahydro-2H-pyran-4-carbaldehyde was used in place ofacetaldehyde and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 466 (M+H)⁺.

Compound 213.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(tetrahydrofuran-2-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used inplace of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) andtetrahydrofuran-2-carbaldehyde was used in place of acetaldehyde. m/z(ES+) 438 (M+H)⁺.

Compound 214.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(tetrahydrofuran-3-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2) and tetrahydrofuran-3-carbaldehyde was used in place ofacetaldehyde. m/z (ES+) 438 (M+H)⁺.

Compound 215.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2) and 4-methyltetrahydro-2H-pyran-4-carbaldehyde (compound 188.3) wasused in place of acetaldehyde. m/z (ES+) 466 (M+H)⁺.

Compound 216.1. 4-(Trifluoromethyl)-1H-imidazole

Into a 1000-mL round-bottom flask, was placed a solution of3,3,3-trifluoro-2-oxopropanal (143 mL, 111.1 mmol) in a solvent mixtureof methanol and water (200/200 mL). An aqueous solution of formaldehyde(350 mL, 116.67 mmol, 35%) and ammonium hydroxide (30 mL, 25%) wereadded to the reaction. The resulting solution was stirred for 2 h atroom temperature, then concentrated under reduced pressure. The solidswere collected by filtration to give 2 g (13%) of the title compound asa white solid.

Compound 216.2.4-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 4-(trifluoromethyl)-1H-imidazole (compound 216.1, 5 g, 36.74 mmol) intetrahydrofuran (100 mL). This was followed by the addition of sodiumhydride (1.6 g, 40.00 mmol, 60%) in portions at 0° C. and stirred for 1h at 0° C. To this was added SEMCl (7.1 mL, 40.36 mmol) dropwise at 0°C. The resulting solution was stirred for 4 h at 0° C., then carefullyquenched with 100 mL of brine. The pH of the solution was adjusted to7-8 with hydrogen chloride (1 M). The aqueous phase was extracted with2×100 mL of ethyl acetate and the combined organic layers were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:5) as eluent to furnish 6 g (61%) of thetitle compound as a light yellow oil.

Compound 216.3.4-(4-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(compound 216.2, 5 g, 18.77 mmol) in tetrahydrofuran (50 mL). This wasfollowed by the addition of n-butyllithium (9 mL, 22.5 mmol, 2.5N inhexane) dropwise at −78° C. and stirred for 1 h at −60° C. To this wasadded dihydro-2H-pyran-4(3H)-one (6 g, 59.93 mmol). The resultingsolution was stirred for 4 h at 0° C. in an ice/salt bath, then quenchedwith 10 mL of water. The resulting solution was diluted with 100 mL ofNH₄Cl (sat.). The aqueous phase was extracted with 2×100 mL of ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:4) as eluent to furnish 6 g (87%) of the title compound as a lightyellow oil.

Compound 216.4.4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol

Into a 25-mL round-bottom flask, was placed4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol(compound 216.3, 2 g, 5.46 mmol), Et₃SiH (2 mL) and trifluoroacetic acid(4 mL). The resulting solution was stirred for 2 h at room temperature.The pH of the solution was adjusted to 8 with sodium hydroxide (1 M).The resulting solution was diluted with 100 mL of brine. The aqueousphase was extracted with 2×100 mL of ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. This resulted in 1.2 g (93%) of the title compound asa white solid.

Compound 216.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol(compound 216.4) was used in place of2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2) and4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used inplace of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2).m/z (ES+) 468 (M+H)⁺.

Compound 217.1.2-(4-Methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol(compound 216.3, 2 g, 5.46 mmol) in tetrahydrofuran (100 mL). This wasfollowed by the addition of sodium hydride (262 mg, 6.55 mmol, 60%) at−70° C. and stirred for 30 min. To this was added MeI (930 mg, 6.55mmol). The resulting solution was stirred for 1 h at room temperature,then carefully quenched with 10 mL of water. The resulting mixture wasdiluted with 50 mL of brine. The aqueous phase was extracted with 2×50mL of ethyl acetate. The combined organic layers were washed with 1×50mL of brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.6 g(77%) of the title compound as light brown oil.

Compound 217.2.2-(4-Methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole

Into a 100-mL round-bottom flask, was placed2-(4-methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(compound 217.1, 1.3 g, 3.42 mmol), trifluoroacetic acid (4 mL), Et₃SiH(2 mL). The resulting solution was stirred overnight at 20° C., thenquenched by the addition of 20 mL of water. The pH of the solution wasadjusted to 8 with sodium hydroxide (1 M). The aqueous phase wasextracted with 2×100 mL of ethyl acetate. The combined organic layerswere washed with 2×50 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. This resulted in 1 g (crude) ofthe title compound as a light yellow oil.

Compound 217.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-2-(4-methoxytetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except2-(4-methoxytetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole(compound 217.2) was used in place of2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2) and4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used inplace of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2).m/z (ES+) 482 (M+H)⁺.

Compound 218.1. 5-Iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole

Into a 50-mL round-bottom flask, was placed a solution of2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2, 1.72 g, 11.46mmol) in CH₃CN (25 mL). NIS (3.87 g, 17.20 mmol) was added to thereaction. The reaction mixture was stirred overnight at 85° C. Thereaction mixture diluted with 50 mL of H₂O and extracted with 3×30 mL ofethyl acetate. The combined organic layers were washed with 2×20 mL ofNa₂S₂O₃(sat.) and 2×20 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. This resulted in 4.32 g (crude)of the title compound as a brown oil.

Compound 218.4-(1-(4-Methyl-3-(2-methyl-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 218.1)was used in place of 2-methyl-1H-imidazole-4-carbonitrile (Compound16.3). m/z (ES+) 425 (M+H)⁺.

Compound 219.1. 2-((Benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazole

Into a 100-mL round-bottom flask, was placed a solution of3,3,3-trifluoro-2-oxopropanal (2 g, 15.87 mmol) in methanol (30 mL).2-(benzyloxy)acetaldehyde (2.8 g, 18.64 mmol) and ammonium hydroxide(25%) (36 mL, 63.48 mmol) were added to the reaction. The reactionmixture was stirred for 15 h at 20° C., then concentrated under reducedpressure. The residue was diluted with 20 mL of H₂O. The aqueous phasewas extracted with 2×30 mL of ethyl acetate and the combined organiclayers were washed with 2×20 mL of brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. This resulted in 4.2 g(crude) of the title compound as a yellow crude oil.

Compound 219.2.2-((Benzyloxy)methyl)-5-iodo-4-(trifluoromethyl)-1H-imidazole

Into a 50-mL round-bottom flask, was placed a solution of2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazole (compound 219.1,1.5 g, 5.85 mmol) in CH₃CN (18 mL). NIS (1.6 g, 7.02 mmol) was added tothe reaction. The reaction mixture was stirred for 15 h at 85° C. Thereaction mixture was diluted with 30 mL of H₂O. The aqueous phase wasextracted with 2×30 mL of ethyl acetate. The combined organic layerswere washed with 2×20 mL of Na₂S₂O₃(sat.) and 2×20 mL of brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:100-1:2) as eluent to furnish 0.7 g (31%) ofthe title compound as a yellow oil.

Compound 219.3. Methyl5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 50-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 2-((benzyloxy)methyl)-5-iodo-4-(trifluoromethyl)-1H-imidazole(compound 219.2, 500 mg, 1.31 mmol) in dioxane (8 mL). Methyl2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound160.1, 450 mg, 1.55 mmol), Pd(dppf)Cl₂ (0.1 g) and an aqueous solutionof potassium carbonate (2 M) (3.25 mL) were added to the reaction. Thereaction mixture was stirred for 1 h at 80° C., then diluted with 20 mLof H₂O. The aqueous phase was extracted with 2×30 mL of ethyl acetate.The combined organic layers were washed with 2×30 mL of brine and driedover anhydrous sodium sulfate. The residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1/20-1/4) as eluentto yield 0.2 g (37%) of the title compound as a light yellow solid.

Compound 219.4. Methyl5-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 50-mL round-bottom flask, under a nitrogen atmosphere, was placeda solution of methyl5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 219.3, 150 mg, 0.36 mmol) in methanol (8 mL). Palladium oncarbon (150 mg, 1.00 equiv) and HCl (4 M, 2 mL) were added to thereaction under a nitrogen atmosphere. To the above hydrogen (1 atm) wasintroduced. The reaction mixture was stirred for 2 h at roomtemperature. The system was purged with nitrogen, then the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure to give 100 mg (85%) of the title compound as a light yellowoil.

Compound 219.5. Methyl5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 50-mL round-bottom flask, was placed a solution of methyl5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 219.4, 100 mg, 0.30 mmol) in ammonium hydroxide (5%) (30 mL).The reaction mixture was stirred for 2 h at 60° C. The reaction mixturewas extracted with 2×50 mL of dichloromethane, the organic layerscombined, dried over anhydrous sodium sulfate and concentrated underreduced pressure. This resulted in 80 mg (92%) of the title compound asa light yellow oil.

Compound 219.6.5-(4-Cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

Into a 25-mL round-bottom flask, was placed a solution of methyl5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 219.6, 100 mg, 0.35 mmol) in methanol (10 mL) and a solutionof NaOH (0.14 g, 3.5 mmol) in water (5 mL). The reaction mixture wasstirred for 15 h at room temperature, then concentrated under reducedpressure. The pH of the solution was adjusted to 1-2 with hydrogenchloride (4 M). The resulting mixture was concentrated under reducedpressure. Methanol (5 mL) was added to the residue. The salt wasfiltered off, and the filtrate was concentrated under reduced pressureto give 200 mg (crude) of the title compound as a light yellow solid.

Compound 219.5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-2-(hydroxymethyl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 219.6) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 430 (M+H)⁺.

Compound 220.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-2-(hydroxymethyl)-1H-imidazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 219.6) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 412 (M+H)⁺.

Compound 221.1.3-(4-Cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound219.6, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1).

Compound 221.4-(1-(4-Methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 3-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 221.1) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 398 (M+H)⁺.

Compound 222.1. 2-(Methoxymethyl)-4-methyl-4,5-dihydro-1H-imidazole

Into a 500-mL round-bottom flask, was placed a solution of2-methoxyacetic acid (20 g, 222.0 mmol) in toluene (200 mL).Propane-1,2-diamine (50 g, 674.5 mmol) was added to the reaction. Thereaction mixture was stirred overnight at 130° C., then concentratedunder reduced pressure. This resulted in 25 g (crude) of the titlecompound as a yellow oil.

Compound 222.2. 2-(Methoxymethyl)-4-methyl-1H-imidazole

Into a 500-mL round-bottom flask, was placed a solution of2-(methoxymethyl)-4-methyl-4,5-dihydro-1H-imidazole (compound 222.1, 19g, 148.4 mmol) in acetonitrile (200 mL). Al₂O₃ (19 g, 182.7 mmol) wasadded to the reaction. This was followed by the addition of potassiumpermanganate (58 g, 367.1 mmol) in several batches at 0° C. The reactionmixture was stirred for 2 h at 0° C., then warmed to room temperatureovernight. The reaction was quenched with 20 mL of sodium sulfite(sat.). The solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. This resulted in 19 g (crude) ofthe title compound as yellow oil.

Compound 222.3. 5-Iodo-2-(methoxymethyl)-4-methyl-1H-imidazole

Into a 100-mL round-bottom flask, was placed a solution of2-(methoxymethyl)-4-methyl-1H-imidazole (compound 222.2, 1.9 g, 15.06mmol) in sodium hydroxide aqueous solution (30 mL, 2M). This wasfollowed by the addition of a solution of iodine (7.7 g, 30.34 mmol) indichloromethane (30 mL). The reaction mixture was stirred for 1 h atroom temperature. The aqueous phase was collected and the pH wasadjusted to 4 with hydrogen chloride (2M). The reaction mixture wasextracted with 4×30 mL of dichloromethane and the organic layerscombined. The resulting mixture was washed with 2×20 mL of sodiumsulfite (sat.) and 3×30 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. This resulted in 1.2 g (32%) ofthe title compound as a yellow solid.

Compound 222.4. Methyl5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 50-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 5-iodo-2-(methoxymethyl)-4-methyl-1H-imidazole (compound 222.3, 400mg, 1.59 mmol) in 1,4-dioxane (15 mL). Methyl2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound160.1, 510 mg, 1.76 mmol), a solution of potassium carbonate (662 mg,4.79 mmol) in water (1 mL) and Pd(dppf)Cl₂ (234 mg, 0.32 mmol) wereadded to the reaction. The reaction mixture was stirred overnight at 90°C. The solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography with dichloromethane/ethyl acetate (1:1) as eluent tofurnish 220 mg (48%) of the title compound as a yellow solid.

Compound 222.5.5-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

Into a 100-mL round-bottom flask, was placed methyl5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 222.4, 220 mg, 0.76 mmol) and HBr (20 mL, 40% in HOAc). Thereaction mixture was stirred overnight at 80° C. The resulting mixturewas concentrated under reduced pressure. This resulted in 190 mg (crude)of the title compound as a brown solid.

Compound 222.6.5-(2-(Cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

Into a 100-mL round-bottom flask, was placed a solution oftrimethylsilanecarbonitrile (376 mg, 3.79 mmol) in acetonitrile (20 mL).Tetrabutylammonium fluoride (3.8 mL, 1 M in THF) was added to thereaction. This was followed by the addition of5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.5, 190 mg, 0.73 mmol), in portions. The reaction mixturewas stirred for 1 h at room temperature, then concentrated under reducedpressure. The residue was purified by silica gel chromatography withethyl acetate/petroleum ether (1:1) as eluent to furnish 190 mg (97%) ofthe title compound as a yellow solid.

Compound 222.4-(1-(5-(2-(Cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

Into a 100-mL round-bottom flask, was placed a solution of5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.6, 190 mg, 0.71 mmol) and HBTU (538 mg, 1.42 mmol) inN,N-dimethylformamide (3 mL). To the above were added a solution of4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4, 160mg, 0.75 mmol) and triethylamine (197 μL, 1.42 mmol) inN,N-dimethylformamide (3 mL) dropwise. The reaction mixture was stirredfor 1 h at room temperature. The crude product (150 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, XBridge Prep C18 OBD Column, 5 m, 19*150 mm; mobile phase, Waterwith 50 mmol NH₄HCO₃ and acetonitrile (30% acetonitrile up to 44% in 7min, hold 44% in 1 min, up to 100% in 1 min, down to 30% in 1 min);Detector, Waters 2489, 254 and 220 nm. This resulted in 45.9 mg (15%) ofthe title compound as a white solid. m/z (ES+) 428 (M+H)⁺.

Compound 223.4-(1-(3-(2-(Cyanomethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound222, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) and 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2) was used in place of4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4). m/z(ES+) 396 (M+H)⁺.

Compound 224.4-(1-(5-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound222, except5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.5) was used in place of5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.6) and 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2) was used in place of4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4). m/z(ES+) 401 (M+H)⁺.

Compound 225.4-(3-Fluoro-1-(5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound222, except5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.5) was used in place of5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.6). m/z (ES+) 419 (M+H)⁺.

Compound 226.1.3-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.5), except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1).

Compound 226.4-(1-(3-(2-(Hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound222, except3-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid(compound 226.1) was used in place of5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 222.6). m/z (ES+) 387 (M+H)⁺.

Compound 227.1. 3-(Benzyloxy)propanal

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed DMSO (5.1mL, 71.79 mmol) in dichloromethane (40 mL). This was followed by theaddition of oxalyl chloride (3.1 mL, 54.16 mmol) dropwise at −78° C. andstirred for 30 min at −78° C. To this was added a solution of3-(benzyloxy)propan-1-ol (4.8 mL, 30.08 mmol) in dichloromethane (10 mL)dropwise at −78° C. The resulting solution was stirred for 1 h at −78°C., then triethylamine (16.5 mL, 118.59 mmol) was added to the reaction.The resulting solution was stirred for 1 h at −78 to −20° C., thenquenched with 50 mL of NH₄Cl (sat.). The aqueous phase was extractedwith 2×50 mL of dichloromethane. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography with EtOAc:PE(1:5) as eluent to furnish 2.0 g (40%) of the title compound as lightyellow oil.

Compound 227.2. 2-(2-(Benzyloxy)ethyl)-5-iodo-4-methyl-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound160.2, except 3-(benzyloxy)propanal (compound 227.1) was used in placeof cyclopropanecarbaldehyde.

Compound 227.3. Methyl3-(2-(2-(benzyloxy)ethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.6, except 2-(2-(benzyloxy)ethyl)-5-iodo-4-methyl-1H-imidazole(compound 227.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5).

Compound 227.4. Methyl3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl3-(2-(2-(benzyloxy)ethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate(compound 227.3, 100 mg, 0.27 mmol) in methanol (10 mL). Palladium oncarbon (100 mg), hydrogen chloride (4M) (2.5 mL) were added to thereaction under N₂. To the above hydrogen was introduced. The reactionmixture was stirred for 3 h at room temperature. The solids werefiltered off and the filtrate was concentrated under reduced pressure.The pH of the solution was adjusted to 7 with sodium bicarbonate (sat.).The resulting solution was extracted with 4×20 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. This resulted in 60 mg (80%) of thetitle compound as a yellow oil.

Compound 227.4-(1-(3-(2-(2-Hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except methyl3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate(compound 227.4) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 401 (M+H)⁺.

Compound 228.5-(5-(3-(4-Cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-1H-imidazole-2-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 14,except 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 414 (M+H)⁺.

Compound 229.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-1H-imidazole-2-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 14,except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 396 (M+H)⁺.

Compound 230.1. 2-(Methoxymethyl)-4,5-dihydro-1H-imidazole

Into a 250-mL round-bottom flask, was placed a solution of2-methoxyacetic acid (20 g, 222.03 mmol) in toluene (60 mL).Ethane-1,2-diamine (133 g, 2.22 mol) was added to the reaction. Thereaction mixture was stirred for 2 days at 130° C. The resulting mixturewas concentrated under reduced pressure. This resulted in 20 g (79%) ofthe title compound as yellow crude oil.

Compound 230.2. 2-(Methoxymethyl)-1H-imidazole

Into a 500-mL 3-neck round-bottom flask, was placed a solution of2-(methoxymethyl)-4,5-dihydro-1H-imidazole (compound 230.1, 20 g, 175.21mmol) in ACN (150 mL). Al₂O₃ (9 g, 87.6 mmol), KMnO4 (27.7 g, 175.21mmol) were added to the reaction. The reaction mixture was stirred for 6h at room temperature, then quenched with 30 mL of Na₂SO₃(sat). Thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. This resulted in 15 g (crude) of the titlecompound as a yellow solid.

Compound 230.3. 4,5-Diiodo-2-(methoxymethyl)-1H-imidazole

Into a 500-mL round-bottom flask, was placed a solution of2-(methoxymethyl)-1H-imidazole (compound 230.2, 15 g, 133.77 mmol) insodium hydroxide aqueous solution (100 mL, 2M). A solution of I₂ (60 g,236.22 mmol) in dichloromethane (100 mL) was added to the reaction. Thereaction mixture was stirred for 3 h at 25° C. The aqueous phase wascollected and diluted with 50 mL of Na₂SO₃(aq). The pH of the solutionwas adjusted to 6-7 with hydrogen chloride (2M). The reaction mixturewas extracted with 3×50 mL of dichloromethane. The aqueous layers werecombined and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/hexane (1:2) aseluent to furnish 4 g (8%) of the title compound as a white solid.

Compound 230.4. 5-Iodo-2-(methoxymethyl)-1H-imidazole

Into a 250-mL round-bottom flask, was placed a solution of4,5-diiodo-2-(methoxymethyl)-1H-imidazole (compound 230.3, 2 g, 5.50mmol) in ethanol (40 mL). A solution of Na₂SO₃ (5.9 g, 46.83 mmol) inwater (80 mL) was added to the reaction. The reaction mixture wasstirred overnight at 90° C. The resulting mixture was concentrated underreduced pressure. The residue was extracted with 3×20 mL ofdichloromethane and the organic layers combined and concentrated underreduced pressure. This resulted in 1 g (76%) of the title compounds asyellow oil.

Compound 230.5. Methyl5-(2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 5-iodo-2-(methoxymethyl)-1H-imidazole (compound 230.4, 70 mg, 0.29mmol) in dioxane (10 mL). Pd(dppf)Cl₂ (22 mg, 0.029 mmol), a solution ofpotassium carbonate (160 mg, 1.16 mmol) in water (2 mL), methyl2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound160.1, 168 mg, 0.58 mmol) were added to the reaction. The reactionmixture was stirred overnight at 90° C., then quenched with 10 mL ofH₂O. The aqueous phase was extracted with 3×10 mL of ethyl acetate andthe combined organic layers were washed with 1×10 mL of brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:1) as eluent to furnish 70 mg (87%) of thetitle compound as a white solid.

Compound 230.6. Methyl5-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl5-(2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound230.5, 70 mg, 0.26 mmol) in chloroform (6 mL). NCS (35 mg, 0.26 mmol)was added to the reaction. The reaction mixture was stirred overnight atroom temperature, then quenched with 1 mL of water. The aqueous phasewas extracted with 2×5 mL of dichloromethane and the combined organiclayers were concentrated under reduced pressure. The residue was appliedonto a silica gel chromatography with ethyl acetate/petroleum ether(1:10) as eluent to yield 30 mg (38%) of the title compound as a whitecrude solid.

Compound 230.7.5-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid

Into a 50-mL round-bottom flask, was placed a solution of methyl5-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 230.5, 20 mg, 0.06 mmol) in HBr (5 mL, 40% in AcOH). Thereaction mixture was stirred overnight at 90° C. The resulting mixturewas concentrated under reduced pressure. This resulted in 10 mg (55%) ofthe title compound as a yellow crude solid.

Compound 230.4-(1-(5-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

Into a 50-mL round-bottom flask, was placed a solution of5-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid(compound 230.6, 180 mg, 0.64 mmol) in N,N-dimethylformamide (15 mL).4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4, 165mg, 0.78 mmol), EDC-HCl (245 mg, 1.28 mmol) and 4-dimethylaminopyridine(310 mg, 2.54 mmol) were added to the reaction. The reaction mixture wasstirred overnight at 25° C. The reaction was then quenched with 5 mL ofwater. The reaction mixture was extracted with 3×10 mL of ethyl acetateand the organic layers combined. The resulting mixture was washed with5×10 mL of brine. The resulting mixture was concentrated under reducedpressure. The crude product (200 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire PrepC18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA andACN (26.0% ACN up to 39.0% in 10 min, up to 100.0% in 2 min, down to26.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in84 mg (30%) of the title compound as a white solid. m/z (ES+) 439(M+H)⁺.

Compound 231.4-(1-(5-(4-Chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound230, except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2)was used in place of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4). m/z (ES+) 421 (M+H)⁺.

Compound 232.1. Ethyl 4-oxobutanoate

Into a 500-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was placed a solution of ethyl4-chloro-4-oxobutanoate (12 g, 72.91 mmol) in tetrahydrofuran (200 mL).The system was purged with nitrogen and palladium on carbon (2 g) wasadded to the reaction. This was followed by the addition oftriethylsilane (16.5 mL, 103.20 mmol) dropwise with stirring at roomtemperature. The reaction mixture was stirred for 2 h at roomtemperature. The solids were filtered off and the filtrate wasconcentrated under reduced pressure to give 18 g (crude) of the titlecompound as a light yellow solid.

Compound 232.2. Methyl 3-(4-methyl-1H-imidazol-2-yl)propanoate

Into a 500-mL round-bottom flask, was placed a solution of ethyl4-oxobutanoate (compound 232.1, 5.4 g, 41.49 mmol) in methanol (125 mL).An aqueous solution of 2-oxopropanal (35%) (28.5 mL, 49.96 mmol) andammonium hydroxide (25%) (100 mL, 165.9 mmol) were added to thereaction. The reaction mixture was stirred for 2 h at 50° C. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by silica gel chromatography with ethyl acetate as eluentto furnish 600 mg (8%) of the title compound as light yellow oil.

Compound 232.3. 3-(4-Methyl-1H-imidazol-2-yl)propanamide

Into a 100-mL round-bottom flask, was placed a solution of ethyl3-(4-methyl-1H-imidazol-2-yl)propanoate (compound 232.2, 500 mg, 2.97mmol) in methanol (10 mL). To the above NH₃(g) was bubbled through thesolution. The reaction mixture was stirred for overnight at 50° C. Theresulting mixture was concentrated under reduced pressure. This resultedin 346 mg (82%) of the title compound as a light yellow solid.

Compound 232.4. 3-(4-Methyl-1H-imidazol-2-yl)propanenitrile

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, were placed a solutionof 3-(4-methyl-1H-imidazol-2-yl)propanamide (compound 232.3, 2 g, 13.06mmol) in toluene (100 mL) and P₂O₅ (2 g, 14.08 mmol). The reactionmixture was stirred for 12 h at 120° C., then quenched with 100 mL ofwater. The aqueous phase was extracted with 2×200 mL of ethyl acetateand the combined organic layers were washed with 2×100 mL of sodiumcarbonate (sat.), dried over sodium sulfate and concentrated underreduced pressure. This resulted in 1 g (57%) of3-(4-methyl-1H-imidazol-2-yl)propanenitrile as light yellow oil

Compound 232.4-(1-(5-(2-(2-Cyanoethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 3-(4-methyl-1H-imidazol-2-yl)propanenitrile (compound 232.4) wasused in place of 2,4-dimethyl-1H-imidazole, methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4), and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 442 (M+H)⁺.

The compounds in TABLE 11 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 222, 223, 231, and 232.

TABLE 11 m/z (ES+) Cpd Name Structure (M + H)⁺  93 4-(1-(3-(4-chloro-2-(cyanomethyl)-1H- imidazol-5-yl)-4- methylbenzoyl) piperidin-4-yl)benzonitrile

444 143 4-(1-(3-(4-chloro-2- (2-cyanoethyl)-1H- imidazol-5-yl)-4-methylbenzoyl) azetidin-3-yl) benzonitrile

430 144 4-(1-(3-(4-chloro-2- (2-cyanoethyl)-1H- imidazol-5-yl)-4-methylbenzoyl) piperidin-4- yl)benzonitrile

458 149 4-(1-(3-(4-chloro-2- (cyanomethyl)-1H- imidazol-5-yl)-4-methylbenzoyl) azetidin-3-yl) benzonitrile

416

Compound 233.4-(1-(3-(2-(2-Cyanoethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 3-(4-methyl-1H-imidazol-2-yl)propanenitrile (compound 232.4) wasused in place of 2,4-dimethyl-1H-imidazole. m/z (ES+) 410 (M+H)⁺.

Compound 234.1. 1H-Imidazole-2-carbonitrile

Into a 1-L round-bottom flask, was placed a solution of1H-imidazole-2-carbaldehyde (5 g, 52.04 mmol) in N,N-dimethylformamide(200 mL). Triethylamine (10.8 mL, 77.97 mmol), hydroxylaminehydrochloride (3.95 g, 56.84 mmol, 1.10 equiv), 1-propanephosphonicanhydride solution and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxidesolution (T₃P) (36.4 g, 114.40 mmol) were added to the reaction. Thereaction mixture was stirred for 4 h at 100° C., cooled and thenquenched with 500 mL of water/ice. The aqueous phase was extracted with3×1 L of ethyl acetate, then the combined organic layers was washed with2×1 L of brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1/2) as eluent tofurnish 2 g (41%) of the title compound as an off-white solid.

Compound 234.2. 5-Iodo-1H-imidazole-2-carbonitrile

Into a 100-mL round-bottom flask, was placed a solution1H-imidazole-2-carbonitrile (compound 234.1, 3.39 g, 36.42 mmol) insodium hydroxide (54.7 mL, 2 M). Iodine (9.26 g, 36.46 mmol) was addedto the reaction. The reaction mixture was stirred for 5 h at roomtemperature. The pH of the solution was adjusted to 5 with HCl (2 M).The aqueous phase was extracted with 3×80 mL of ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1/1.5) as eluentto furnish 1.02 g (13%) of the title compound as a white solid.

Compound 234.3. Methyl 3-(2-cyano-1H-imidazol-5-yl)-4-methylbenzoate

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 5-iodo-1H-imidazole-2-carbonitrile (compound 234.2, 700 mg, 3.20mmol) in a solvent mixture of DME and H₂O (30/3 mL). Methyl4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4,1.06 g, 3.84 mmol), K₃PO₄ (2.71 g, 12.8 mmol), Xphos (152 mg, 0.32mmol), Pd(PPh3)₄ (369 mg, 0.32 mmol) were added to the reaction. Thereaction mixture was stirred overnight at 90° C., then concentratedunder reduced pressure. The residue was diluted with 50 mL of ethylacetate, then was washed with 3×20 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by a silica gel chromatography with ethyl acetate/petroleumether (1/2) as eluent to furnish 160 mg (21%) of the title compound as awhite solid.

Compound 234.4. Methyl3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoate

Into a 50-mL round-bottom flask, was placed a solution of methyl3-(2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.3, 290 mg,1.20 mmol) in a solvent mixture of DMF and CHCl₃ (4/20 mL). NCS (161 mg,1.21 mmol, 1.00 equiv) was added to the above reaction mixture. Thereaction mixture was stirred overnight at room temperature, then wasconcentrated under reduced pressure. The residue was diluted with 30 mLof EtOAc, then was washed with 3×15 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1/10-1/7) as eluent to furnish 160 mg (48%) of the title compound aslight yellow oil.

Compound 234.5. 3-(4-Chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoicacid

Into a 25-mL round-bottom flask, was placed a solution of methyl3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.4,130 mg, 0.47 mmol) in methanol (4 mL). Then a solution of LiOH (45.4 mg,1.90 mmol) in water (2 mL) was added to the reaction. The reactionmixture was stirred overnight at 30° C., then was concentrated underreduced pressure. The pH of the solution was adjusted to 3 with hydrogenchloride (1M) and was concentrated under reduced pressure. Methanol (5mL) was added to the residue. The salt was filtered off, and thefiltrate was concentrated under reduced pressure to give 150 mg (crude)of the title compound as a white solid.

Compound 234.4-Chloro-5-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-2-carbonitrile

Into a 25-mL round-bottom flask, was placed a solution of3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoic acid (compound234.5, 60 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL).4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 61 mg, 0.27mmol), HBTU (131 mg, 0.35 mmol), DIEA (123 μL, 0.69 mmol) were added tothe reaction. The reaction mixture was stirred for 30 min at 15° C. Thereaction mixture was diluted with 40 mL of EtOAc, then was washed with2×30 mL of brine and 2×30 mL of NH₄Cl (sat.), dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct (160 mg) was purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column,5 m, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and MeCN (49.0% MeCNup to 62.0% in 7 min, up to 100.0% in 3 min, down to 49.0% in 1 min);Detector, Waters 2489, 254 and 220 nm. This resulted in 25.1 mg (25%) ofthe title compound as a white solid. m/z (ES+) 430 (M+H)⁺.

Compound 235.4-Chloro-5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-2-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound234, except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2)was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2). m/z (ES+) 402 (M+H)⁺.

Compound 236.1. 5-Iodo-2-methyl-1H-imidazole-4-carbaldehyde

Into a 100-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was placed a solution of2-methyl-1H-imidazole-4-carbaldehyde (1.5 g, 13.6 mmol) in CH₃CN (50mL). NIS (3.7 g, 16.4 mmol) was added to the reaction. The reactionmixture was stirred for 4 h at 80° C., then was concentrated underreduced pressure. The residue was purified by silica gel chromatographywith ethyl acetate/petroleum ether (3:1) as eluent to furnish 2.11 g(66%) of the title compound as a yellow solid.

Compound 236.2. Methyl5-(4-formyl-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 5-iodo-2-methyl-1H-imidazole-4-carbaldehyde (compound 236.1, 600 mg,2.54 mmol) in dioxane (30 mL). Methyl2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound160.1, 800 mg, 2.76 mmol), a solution of potassium carbonate (1.8 g,13.0 mmol) in water (10 mL), and Pd(dppf)Cl₂ (400 mg, 0.55 mmol, 0.20equiv) were added to the reaction. The reaction mixture was stirred forovernight at 80° C., then was quenched with 20 mL of water. The aqueousphase was extracted with 2×100 mL of ethyl acetate and the combinedorganic layers were washed with 2×50 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(3:1) as eluent to furnish 400 mg (58%) of the title compound as a lightyellow solid.

Compound 236.3. Methyl5-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate

Into a 50-mL round-bottom flask, was placed a solution of methyl5-(4-formyl-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound236.2, 400 mg, 1.47 mmol) in methanol (20 mL). This was followed by theaddition of NaBH₄ (100 mg, 2.64 mmol) in several batches at 0° C. Thereaction mixture was stirred for 1 h at room temperature, then was usedfor next step directly.

Compound 236.4-(1-(5-(4-(Hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except methyl5-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate(compound 236.3) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 401 (M+H)⁺.

Compound 237.1. Methyl3-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound236.3, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1).

Compound 237.4-(1-(3-(4-(Hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except methyl3-(4-(hydroxymethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoate(compound 237.1) was used in place of methyl3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z(ES+) 387 (M+H)⁺.

Compound 238.1. 2-Cyclopropyl-1H-imidazole

Into a 500-mL round-bottom flask, was placed a solution ofcyclopropanecarbaldehyde (10.7 mL, 142.7 mmol) in methanol (60 mL). Anaqueous solution of oxalaldehyde (18.0 mL, 157.1 mmol, 40%) was added tothe reaction. This was followed by the addition of NH₄OH (89 mL, 571.4mmol) dropwise at 0° C. in 30 min. The reaction mixture was stirredovernight at room temperature, then concentrated under reduced pressure.The resulting solution was extracted with 3×100 mL of ethyl acetate. Thecombined organic layers were washed with 2×30 mL of brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thisresulted in 12 g (crude) of the title compound as a brown solid.

Compound 238.2. 2-Cyclopropyl-N,N-dimethyl-1H-imidazole-1-sulfonamide

Into a 500-mL round-bottom flask, was placed a solution of2-cyclopropyl-1H-imidazole (compound 238.1, 12 g, 110.9 mmol) indichloromethane (60 mL). Triethylamine (31.4 mL, 225.3 mmol),N,N-dimethylsulfamoyl chloride (13.2 mL, 121.87 mmol, 1.10 equiv) wereadded to the reaction. The reaction mixture was stirred for 4 h at roomtemperature, then quenched with 20 mL of water. The aqueous phase wasextracted with 3×100 mL of dichloromethane. The combined organic layerswere washed with 2×20 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1:4) as eluent tofurnish 16 g (67%) of the title compound as a white solid.

Compound 238.3. 2-Cyclopropyl-1H-imidazole-4-carbaldehyde

Into a 500-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 2-cyclopropyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (compound238.2, 5 g, 23.23 mmol) in tetrahydrofuran (100 mL). This was followedby the addition of n-butyllithium (11.2 mL, 2.5M in THF) dropwise at−78° C. over a period of 30 min. To this was added DMF (11.8 mL, 152.55mmol). The resulting solution was stirred for 30 min at −50° C., thenhydrogen chloride (50 mL, 1M) was added. The reaction mixture wasstirred for 2 h at room temperature. The pH of the solution was adjustedto 7-8 with sodium bicarbonate (sat). The resulting solution wasextracted with 3×30 mL of ethyl acetate and the organic layers combined.The resulting mixture was washed with 2×10 mL of brine. The mixture wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. This resulted in 3 g (97%) of the title compound as a whitesolid.

Compound 238.4-(1-(3-(2-Cyclopropyl-4-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound236, except 2-cyclopropyl-1H-imidazole-4-carbaldehyde (compound 238.3)was used in place of 2-methyl-1H-imidazole-4-carbaldehyde and methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1). m/z (ES+) 413 (M+H)⁺.

Compound 239.1. Ethyl 4-methyl-1H-imidazole-2-carboxylate

Into a 50-mL round-bottom flask, was placed a solution of ethyl2-oxoacetate (400 mg, 3.92 mmol) in methanol (4 mL). A aqueous solutionof 2-oxopropanal (565 mg, 3.92 mmol, 50%), ammonia (25%) (8.8 mL, 15.68mmol) were added to the reaction. The reaction mixture was stirred forovernight at room temperature, then was concentrated under reducedpressure. The residue was purified by silica gel chromatography withethyl acetate/petroleum ether (1/1) as eluent to furnish 200 mg (33%) ofthe title compound as a yellow solid.

Compound 239.2. Ethyl 5-iodo-4-methyl-1H-imidazole-2-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of ethyl4-methyl-1H-imidazole-2-carboxylate (compound 239.1, 100 mg, 0.65 mmol)in CH₃CN (10 mL). NIS (218 mg, 0.97 mmol) was added to the reaction. Thereaction mixture was stirred for overnight at room temperature, thenconcentrated under reduced pressure. The residue was dissolved with 30mL of EtOAc, then was washed with 2×20 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. This resulted in80 mg (44%) of the title compound as a yellow solid.

Compound 239.3. 5-Iodo-4-methyl-1H-imidazole-2-carboxylic acid

Into a 100-mL round-bottom flask, was placed a solution of ethyl5-iodo-4-methyl-1H-imidazole-2-carboxylate (compound 239.2, 200 mg, 0.71mmol) in methanol (4 mL). A solution of sodium hydroxide (114 mg, 2.85mmol) in water (2 mL) was added to the reaction. The reaction mixturewas stirred for 2 h at 60° C. The pH of the solution was adjusted to 1-2with hydrogen chloride (1 M). The resulting mixture was concentratedunder reduced pressure. Methanol (5 mL) was added to the residue. Thesalt was filtered off and the filtrate was concentrated under reducedpressure to give 290 mg (crude) of the title compound as a white solid.

Compound 239.4. 5-Iodo-N,N,4-trimethyl-1H-imidazole-2-carboxamide

Into a 100-mL round-bottom flask, was placed a solution of5-iodo-4-methyl-1H-imidazole-2-carboxylic acid (compound 239.3, 200 mg,0.79 mmol) in N,N-dimethylformamide (4 mL). HBTU (602 mg, 1.59 mmol),dimethylamine hydrochloride (96 mg, 1.18 mmol) and triethylamine (552μL, 3.96 mmol) were added to the reaction. The reaction mixture wasstirred for 3 h at room temperature, then diluted with 50 mL of EtOAc.The organic layer was washed with 2×20 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. This resulted in150 mg (68%) of the title compound as yellow oil.

Compound 239.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-N,N,4-trimethyl-1H-imidazole-2-carboxamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-iodo-N,N,4-trimethyl-1H-imidazole-2-carboxamide (compound239.4) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound5.5) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 442 (M+H)⁺.

Compound 240.1. 5-Iodo-4-methyl-2-(trifluoromethyl)-1H-imidazole

Into a 250-mL round-bottom flask, was placed a solution of4-methyl-2-(trifluoromethyl)-1H-imidazole (compound 14.1, 4.41 g, 29.38mmol) in CH₃CN (100 mL). NIS (6.6 g, 29.34 mmol) was added to thereaction. The reaction mixture was stirred overnight at roomtemperature, then concentrated under reduced pressure. The reactionmixture was diluted with 300 mL of EtOAc. The organic layer was washedwith 3×150 mL of brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1/30-1/20) aseluent to furnish 2.125 g (26%) of the title compound as a light yellowsolid.

Compound 240.4-(1-(4-Methyl-3-(4-methyl-2-(trifluoromethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 16,except 5-iodo-4-methyl-2-(trifluoromethyl)-1H-imidazole (compound 240.1)was used in place of 5-iodo-2-methyl-1H-imidazole-4-carbonitrile(compound 16.4). m/z (ES+) 425 (M+H)⁺.

Compound 241.1. 5-Iodo-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound44.3, except tetrahydro-2H-pyran-4-carbaldehyde was used in place ofcyclopropanecarbaldehyde.

Compound 241.2. Methyl4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoate

Into a 50-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 5-iodo-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (compound 241.1, 400mg, 1.44 mmol) in dioxane (15 mL). Methyl4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4,397 mg, 1.44 mmol), potassium carbonate (993 mg, 7.18 mmol), water (1.5mL) and Pd(dppf)C12 (105 mg, 0.14 mmol, 0.10 equiv) were added to thereaction. The reaction mixture was stirred overnight at 90° C., thendiluted with 120 mL of EtOAc. The organic layer was washed with 3×40 mLof brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith ethyl acetate as eluent to furnish 260 mg (60%) of the titlecompound as red oil.

Compound 241.3. Methyl3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoate

Into a 25-mL round-bottom flask, was placed a solution of methyl4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoate(compound 241.2, 260 mg, 0.87 mmol) in chloroform (3 mL). NCS (116 mg,0.87 mmol) was added to the reaction. The reaction mixture was stirredfor 4 h at 25° C., then concentrated under reduced pressure. The residuewas dissolved in 50 mL of EtOAc, then was washed with 3×20 mL of brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. This resulted in 313 mg (crude) of the title compound as brownoil.

Compound 241.4.3-(4-Chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoicacid

Into a 50-mL round-bottom flask, was placed a solution of methyl3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 241.3, 290 mg, 0.87 mmol) in methanol (6 mL). Then a solutionof sodium hydroxide (139 mg, 3.48 mmol) in water (3 mL) was added to thereaction. The reaction mixture was stirred for 1 h at 60° C., thenconcentrated under reduced pressure. The pH of the solution was adjustedto 1 with hydrogen chloride (2 M). The resulting mixture wasconcentrated under reduced pressure. Methanol (10 mL) was added to theresidue. The salt was filtered off, and the filtrate was concentratedunder reduced pressure to give 300 mg of the title compound as a brownsolid.

Compound 241.4-(1-(3-(4-Chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 25-mL round-bottom flask, was placed a solution of3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 241.4, 150 mg, 0.47 mmol) in N,N-dimethylformamide (3mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 91 mg,0.47 mmol), EDC-HCl (180 mg, 0.94 mmol), 4-dimethylaminopyridine (114mg, 0.93 mmol) were added to the reaction. The reaction mixture wasstirred for 3 h at 25° C., then diluted with 80 mL of EtOAc. The organiclayer was washed with 3×50 mL of brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude product (300mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 μm,19*150 mm; mobile phase, WATER WITH 0.05% TFA and ACN (25.0% ACN up to39.0% in 8 min, hold 39.0% in 1 min, up to 100.0% in 3 min, down to25.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in133.3 mg (62%) of the title compound as a light yellow solid. m/z (ES+)461 (M+H)⁺.

Compound 242.1. Methyl5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound59.2, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 259 (M+H)⁺.

Compound 242.2. 5-(3,4-Dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound59.3, except methyl5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 242.1)was used in place of methyl3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate (compound 59.2). m/z(ES+) 245 (M+H)⁺.

Compound 242.4-(1-(5-(3,4-Dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 59,except 5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid(compound 242.2) was used in place of3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3).m/z (ES+) 385 (M+H)⁺.

Compound 243.4-(1-(5-(3,4-Dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 60,except 5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid(compound 242.2) was used in place of3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3).m/z (ES+) 403 (M+H)⁺.

Compound 244.1.1-Benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Into a 100-mL three neck round-bottom flask, was placed a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.60 g,18.6 mmol) in THF (50 mL). Sodium hydride (742 mg, 18.6 mmol, 60%dispersion in mineral oil) was carefully added in portions at 0° C. Theresulting mixture was stirred for 30 min at 0° C., then benzyl bromide(2.21 mL, 18.6 mmol) was added. The resulting mixture was stirredovernight at room temperature, then carefully quenched with water (10mL). The pH of the mixture was adjusted to 9-10 with aqueous HCl (2 M)and the aqueous phase was extracted with EtOAc (300 mL). The combinedorganic layers were washed with brine (2×150 mL), dried (Na₂SO₄),filtered and concentrated under vacuum. The residue was purified bysilica gel chromatography with ethyl acetate/petroleum ether (1/2) aseluent to yield the title compound as a yellow oil (3.47 g, 66%).

Compound 244.2. 1-Benzyl-1H-pyrazol-4-ol

Into a 100-mL three neck round-bottom flask, was placed a solution of1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(compound 244.1, 3.47 g, 12.2 mmol) in tetrahydrofuran (35 mL). Sodiumhydroxide (980 mg, 24.5 mmol) was added and then the mixture was cooledto 0° C. Hydrogen peroxide (2.51 mL, 24.4 mmol) was carefully addeddrop-wise and the resulting mixture was stirred for 2 h at roomtemperature. The reaction was carefully quenched with aqueousNa₂S₂O₃(sat.) (20 mL). The aqueous phase was extracted with EtOAc (300mL) and the combined organic layers were washed with brine (2×150 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1/1) as eluent to furnish the title compound asa white solid (1.64 g, 77%).

Compound 244.3. 1-Benzyl-4-methoxy-1H-pyrazole

Into a 100-mL round-bottom flask, was placed a solution of1-benzyl-1H-pyrazol-4-ol (compound 244.2, 1.40 g, 8.04 mmol) inN,N-dimethylformamide (20 mL). Iodomethane (703 μL, 11.3 mmol) andCs₂CO₃ (3.68 g, 11.3 mmol,) were added and the resulting mixture wasstirred for 3 h at room temperature. The mixture was concentrated underreduced pressure, then diluted with EtOAc (200 mL). The mixture waswashed with brine (3×80 mL), and the organic layer was dried (Na₂SO₄),filtered and concentrated under reduced pressure to obtain the titlecompound as a yellow oil (1.30 g, 86%).

Compound 244.4. 4-Methoxy-1H-pyrazole

Into a 100-mL round-bottom flask, was placed a solution of1-benzyl-4-methoxy-1H-pyrazole (compound 244.3, 666 mg, 3.54 mmol) inmethanol (10 mL). Hydrogen chloride (1 M, 1 mL) and Pd(OH)₂/C (20 wt %,670 mg) were added and the mixture was purged with nitrogen then chargedwith hydrogen. The mixture was stirred under hydrogen overnight at roomtemperature, then purged with nitrogen. The solids were removed byfiltration and the filtrate was concentrated under reduced pressure toobtain the title compound as a brown oil (0.36 g, crude).

Compound 244.5. 3-Iodo-4-methoxy-1H-pyrazole

Into a 50-mL round-bottom flask, was placed 4-methoxy-1H-pyrazole(compound 244.4, 360 mg, 3.67 mmol) in N,N-dimethylformamide (4 mL). NIS(830 mg, 3.69 mmol) was added portion-wise and the resulting mixture wasstirred overnight at room temperature. The mixture was diluted withethyl acetate (40 mL), then washed with brine (3×10 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:10) as the eluent to obtain the title compound as a white solid (0.54g, 66%).

Compound 244.6. Methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate

Into a 50-mL three neck round-bottom flask, purged and maintained withnitrogen, was placed a solution of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (414mg, 1.50 mmol) in dioxane (6 mL). Potassium carbonate (2 M, 2.5 mL, 5.00mmol), 3-iodo-4-methoxy-1H-pyrazole (compound 244.5, 224 mg, 1.00 mmol),Pd(dppf)Cl₂ (73 mg, 0.10 mmol) were added to the reaction and theresulting mixture was stirred overnight at 90° C. The resulting mixturewas cooled, then diluted with EtOAc (80 mL) and washed with brine (2×30mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was purified by a silica gel column chromatography withethyl acetate/petroleum ether (1/1) as eluent to obtain the titlecompound as a yellow oil (180 mg, 73%).

Compound 244.7. 3-(4-Methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid

Into a 50-mL round-bottom flask, was placed a solution of methyl3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6, 180 mg,0.73 mmol) in methanol (4 mL). Sodium hydroxide (117 mg, 2.92 mmol) inwater (2 mL) was added and the resulting solution was stirred for 3 h at60° C., then concentrated under reduced pressure. The pH of the residuewas adjusted to 1 with aqueous hydrogen chloride (1 M), thenconcentrated under reduced pressure. Methanol (5 mL) was added to theresidue and the solids were filtered from the solution. The filtrate wasconcentrated under reduced pressure to obtain the title compound as alight yellow solid (353 mg, crude).

Compound 244.4-(1-(3-(4-Methoxy-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 25-mL round-bottom flask, was placed a solution of3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7, 60mg, 0.26 mmol) in N,N-dimethylformamide (2 mL).4-(Azetidin-3-yl)benzonitrile hydrochloride (75 mg, 0.39 mmol), EDC-HCl(99 mg, 0.52 mmol), and 4-dimethylaminopyridine (63 mg, 0.52 mmol) wereadded and the solution was stirred for 2 h at room temperature. Thereaction was diluted with EtOAc (30 mL) and washed with brine (3×15 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude product (150 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBDColumn, 5 μm, 19*150 mm; mobile phase, water with 0.05% TFA and CH₃CN(35.0% CH₃CN up to 50.0% in 10 min, up to 100% in 1 min, down to 35.0%in 2 min); Detector, UV 254 & 220 nm. The fractions contained pureproduct were combined and lyophilized to obtain the title compound as anoff-white solid (44.3 mg, 46%). m/z (ES+) 373 (M+H⁺).

Compound 245.4-(1-(3-(4-Methoxy-1H-pyrazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 401 (M+H⁺).

Compound 246.4-(3-Fluoro-1-(3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 391 (M+H⁺).

Compound 247.4-(1-(5-(4-Methoxy-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 387 (M+H⁺).

Compound 248.1. 1-Benzyl-4-bromo-3-methyl-1H-pyrazole

Into a 500-mL 3-neck round-bottom flask, was placed a solution of4-bromo-3-methyl-1H-pyrazole (20.0 g, 124 mmol) in N,N-dimethylformamide(100 mL). The system was purged with nitrogen, then the solution wascooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 10.0 g,250 mmol) was carefully added portion-wise and then the resultingmixture was stirred for 30 min at room temperature. The mixture wascooled to 0° C., then benzyl bromide (22.1 mL, 186 mmol) was addeddrop-wise and the resulting mixture was stirred overnight at roomtemperature. The mixture was carefully quenched by drop-wise addition ofwater (40 mL), then the mixture was extracted with ethyl acetate (3×200mL). The combined organic extracts were washed with brine (4×100 mL),dried (Na₂SO₄), filleted and concentrated under reduced pressure toobtain the title compound as a yellow oil (24.9 g, 80%).

Compound 248.2.1-Benzyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 1-benzyl-4-bromo-3-methyl-1H-pyrazole (compound 248.1, 24.5 g, 97.6mmol) in DMSO (160 mL).4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (29.9 g, 118mmol), Pd(dppf)Cl₂ (7.16 g, 9.79 mmol) and KOAc (28.8 g, 293 mmol) wereadded. The resulting mixture was stirred overnight at 90° C., thencooled and quenched with water (100 mL). The mixture was extracted withethyl acetate (3×100 mL) and the combined organic extracts were washedbrine (4×100 mL), dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by a silica gel column withethyl acetate/petroleum ether (1:20) as eluent to obtain the titlecompound as a yellow oil (10.64 g, 37%).

Compound 248.4-(1-(3-(4-Methoxy-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except1-benzyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(compound 248.2) was used in place of1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(compound 244.1). m/z (ES+) 387 (M+H⁺).

Compound 249.1. Ethyl 2-methyl-3-oxopropanoate

Into a 500-mL 3-neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution of ethylpropionate (11.3 mL, 97.9 mmol) in tetrahydrofuran (160 mL). Thesolution was cooled to 0° C., then sodium hydride (4.1 g, 103 mmol, 60%dispersion in mineral oil) was added in portions. The mixture wasstirred at 0° C. for 10 min, then ethyl formate (7.92 mL, 98.5 mmol) wasadded and the resulting mixture was stirred overnight at roomtemperature. The reaction was carefully quenched water (100 mL) bydrop-wise addition and the mixture was extracted with ethyl acetate(2×100 mL). The combined organic extracts were dried (Na₂SO₄), filteredand concentrated under reduced pressure. The crude product was purifiedby distillation under reduced pressure (50 mm Hg) and the fractionbetween 70-80° C. was collected to obtain the title compound as acolorless liquid (3.0 g, 24%).

Compound 249.2. 1-Benzyl-4-methyl-1H-pyrazol-5-ol

Into a 100-mL round-bottom flask, was placed a solution of ethyl2-methyl-3-oxopropanoate (compound 249.1, 500 mg, 3.84 mmol) in ethanol(15 mL). Benzylhydrazine hydrochloride (730 mg, 4.66 mmol) was added andthe reaction was stirred for 5 h at 80° C., then concentrated underreduced pressure. The residue was purified by a silica gelchromatography with dichloromethane/methanol (30:1) as eluent to obtainthe title compound as a yellow oil (430 mg, 59%).

Compound 249.3. 1-Benzyl-5-methoxy-4-methyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed a solution of1-benzyl-4-methyl-1H-pyrazol-5-ol (compound 249.2, 2.0 g, 10.6 mmol) inN,N-dimethylformamide (15 mL). The solution was cooled to 0° C., thensodium hydride (600 mg, 15.00 mmol, 60% dispersion in mineral oil) wasadded in portions and the resulting mixture was stirred for 10 min at 0°C. Iodomethane (878 μL, 14.1 mmol) was added and the resulting mixturewas stirred for 3 h at room temperature, then carefully quenched bydrop-wise addition of water (10 mL). The mixture was extracted ethylacetate (3×40 mL) and the combined organic extracts were washed withbrine (3×20 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified by a silica gel chromatography withethyl acetate/petroleum ether (1:8) as eluent to obtain the titlecompound as a yellow oil (500 mg, 23%).

Compound 249.4. 5-Methoxy-4-methyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed a solution of1-benzyl-5-methoxy-4-methyl-1H-pyrazole (compound 249.3, 300 mg, 1.48mmol) in DMSO (10 mL). Potassium tert-butoxide (11 mL, 11 mmol, 1 M inTHF) was added slowly and the resulting mixture was stirred overnight atroom temperature under dry air conditions. The pH of the solution wasadjusted to 7-8 with aqueous HCl (2M), diluted with additional water andthe mixture was extracted with ethyl acetate (3×30 mL). The combinedorganic extracts were washed with brine (3×20 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:8) as eluent to obtain the title compound as a yellow oil (150 mg,90%).

Compound 249.4-(1-(5-(3-Methoxy-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 5-methoxy-4-methyl-1H-pyrazole (compound 249.4) was used inplace 4-methoxy-1H-pyrazole (compound 244.4) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) m/z (ES+) 401 (M+H⁺).

Compound 250.1. 5-Iodo-4-methyl-1H-pyrazole

NIS (5.62 g, 24.98 mmol) was added portion-wise to a solution of4-methyl-1H-pyrazole (Aldrich, 2.05 g, 24.97 mmol) in acetonitrile (50mL). The mixture was heated at 60° C. for 30 minutes, then cooled toroom temperature. The mixture was partitioned between EtOAc (300 mL) andwater (80 mL). The organic layer was washed with saturated sodiumthiosulfate (50 mL), brine (50 mL), dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexanes:EtOAc, 5:1) to yield the title compound as awhite solid (2.3 g, 45%). m/z (ES+) 209 (M+H)⁺.

Compound 250.2.5-Iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

NaH (0.48 g, 12.2 mmol, 60%) was added to a solution of5-iodo-4-methyl-1H-pyrazole (compound 250.1, 2.3 g, 11.1 mmol) in THF(20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then2-(trimethylsilyl)ethoxymethyl chloride (2.15 mL, 12.2 mmol) was added.The resulting mixture was stirred at room temperature for 3 hours, andthen carefully quenched with a small amount of water and partitionedbetween EtOAc (200 mL) and water (50 mL). The organic layer was washedwith brine (50 mL), dried (MgSO₄) and concentrated under reducedpressure. The residue was purified with by silica gel columnchromatography (hexanes:EtOAc, 10:1) to yield the title compound as alight yellow oil (3.15 g, 84%). m/z (ES+) 339 (M+H)⁺.

Compound 250.3. Methyl2,4-dimethyl-5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzoate

Methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1, 2.7 g, 9.32 mmol),5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(compound 250.2, 3.15 g, 9.32 mmol), K₂CO₃ (6.42 g, 46.6 mmol) andPdCl₂(dppf) CH₂Cl₂ (0.76 g, 0.93 mmol) were added to a round bottomflask. The flask was purged with argon, then dioxane (50 mL) and water(20 mL) were added and the mixture was heated at 90° C. for 16 hours.The mixture was cooled to room temperature and then partitioned betweenEtOAc (300 mL) and water (50 mL). The organic layer was washed withbrine (50 mL), dried (MgSO₄) and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexanes:EtOAc, 10:1) to yield the title compound as a light brown oil(3.0 g, 86%). m/z (ES+) 375 (M+H)⁺.

Compound 250.4. Methyl5-(3-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate

To a solution of methyl2,4-dimethyl-5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzoate (compound 250.3, 3.0 g, 8.02 mmol) inacetonitrile (20 mL) was added NCS (1.07 g, 8.02 mmol). The mixture wasstirred at room temperature overnight, then partitioned between EtOAc(200 mL) and water (50 mL). The organic layer was washed with saturatedsodium thiosulfate (50 mL), brine (50 mL), dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified with bysilica gel column chromatography (hexanes:EtOAc, 20:1) to yield thetitle compound as a colorless oil (2.0 g, 61%). m/z (ES+) 409 (M+H)⁺.

Compound 250.5. Methyl5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate

TFA (10 mL) was carefully added to a solution of5-(3-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 250.4, 2.0 g,4.90 mmol) in CH₂Cl₂ (10 mL). The mixture was stirred at roomtemperature for 2 hours, then the solvents were removed under reducedpressure. The residue was dissolved in EtOAc (200 mL) and washed withsat. NaHCO₃ (50 mL), brine (50 mL), dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexanes:EtOAc, 4:1) to yield the title compound as whitefoam (1.13 g, 83%). m/z (ES+) 279 (M+H)⁺.

Compound 250.6.5-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid

NaOH (2 M in water, 8 mL, 16 mmol) was added to a solution of methyl5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound250.5, 1.10 g, 3.96 mmol) in MeOH (10 mL). The mixture was stirred atroom temperature overnight and the solvents were removed under thereduced pressure. The residue was cooled to 0° C. and acidified to pH˜3-4 with 1M HCl in water. The resulting white solids were filtered,washed with water and dried to give the title compound as a white solid(1.07 g, 90%). m/z (ES+) 265 (M+H)⁺.

Compound 250.4-(1-(5-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid(compound 250.6) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7).m/z (ES+) 405 (M+H)⁺.

Compound 251.4-(1-(5-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid(compound 250.6) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7)and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4)was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 423 (M+H)⁺.

Compound 252.4-(1-(3-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)-3-fluoroazetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound250, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 409 (M+H⁺).

Compound 253.4-(1-(3-(3-Chloro-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound250, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used in place of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) and 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 419 (M+H⁺).

Compound 136.4-(1-(5-(4-Chloro-3-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 51,except 5-bromo-3-methyl-1H-pyrazole was used in place of5-iodo-1H-pyrazole. m/z (ES+) 405 (M+H⁺).

Compound 255.1. 5-(Methoxycarbonyl)-2,4-dimethylbenzoic acid

A solution of 5-iodo-2,4-dimethylbenzoic acid (5.0 g, 18.1 mmol) inmethanol (45 mL) was added to a 100-mL pressure tank reactor (40 atm).Triethylamine (7.57 mL, 54.3 mmol) and Pd(dppf)Cl₂ (1.3 g, 1.8 mmol)were added and the system was purged with nitrogen. CO (g) was verycarefully introduced. Caution: carbon monoxide is a very toxic gas. Thereaction was heated at 90° C. overnight, then cooled to room temperatureand very carefully evacuated. The solvent was removed under reducedpressure. The pH of the residue was adjusted to 1-2 with aq HCl (6 M),diluted with additional water, then extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed brine (3×10 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by a silica gel column with ethyl acetate/hexane (1:1) aseluent to obtain the title compound as a red solid (2.3 g, 61%).

Compound 255.2. Methyl 5-(chlorocarbonyl)-2,4-dimethylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of5-(methoxycarbonyl)-2,4-dimethylbenzoic acid (compound 255.1, 100 mg,0.48 mmol) in dichloromethane (10 mL). Oxalyl chloride (80 μL, 0.95mmol) was added and the resulting solution was stirred for 1 h at 40°C., then concentrated under reduced pressure to obtain the titlecompound as a white solid (80 mg, 74%).

Compound 255.3. Methyl5-(2-(difluoromethylene)butanoyl)-2,4-dimethylbenzoate

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of argon, was placed a solution of2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.00 g, 3.93 mmol) in THF(30 mL). The solution was cooled to −78° C., then n-BuLi (5.0 mL, 1.6 Min hexane, 8.0 mmol) was added drop-wise and the mixture was stirred at−78° C. for 40 min. Triethylborane (TEB) (5.0 mL, 1 M in THF, 5.0 mmol)was slowly added and the mixture was stirred at −78° C. for 1 h, then atroom temperature for 3 h. The solution was cooled to 0° C., thenhexamethylphosphoramide (HMPA) (6 mL) and CuI (1.5 g, 7.9 mmol) wereadded and the mixture was stirred at room temperature for 30 min. Asolution of methyl 5-(chlorocarbonyl)-2,4-dimethylbenzoate (compound255.2, 530 mg, 2.34 mmol) in THF (30 mL) was carefully added and stirredat room temperature for 30 min. The pH of the mixture was carefullyadjusted to 7 with aqueous H₃PO₄ and the mixture was partitioned. Theaqueous phase was extracted with ethyl acetate (3×20 mL) and thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with ethylacetate/petroleum ether (1:40) as eluent to obtain the title compound asa yellow oil (250 mg, 38%).

Compound 255.4. Methyl5-(4-ethyl-3-fluoro-1H-pyrazol-5-yl)-2,4-dimethylbenzoate

Into a 250-mL round-bottom flask, was placed a solution of methyl5-(2-(difluoromethylene)butanoyl)-2,4-dimethylbenzoate (compound 255.3,175 mg, 0.62 mmol) in THF (100 mL). At room temperature, hydrazinehydrate (120 μL, 2.48 mmol) was added followed by trifluoroacetic acid(144 μL, 1.88 mmol), then the solution was stirred at 50° C. for 1.5 h.The reaction was cooled to room temperature, carefully diluted withwater and the mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue was purified by a silica gel columnwith ethyl acetate/hexane (1:10) as eluent to obtain the title compoundas a yellow oil (90 mg, 53%).

Compound 255.4-(1-(5-(4-Ethyl-3-fluoro-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except methyl5-(4-ethyl-3-fluoro-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound255.4) was used in place methyl3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6). m/z(ES+) 403 (M+H⁺).

Compound 256.1. 3-Iodo-1H-pyrazole-4-carbonitrile

Into a 100-mL three neck round-bottom flask, was placed a solution of3-amino-1H-pyrazole-4-carbonitrile (1.00 g, 9.25 mmol) in hydrogenchloride (12 M, 8 mL). The reaction solution was cooled to 0° C., then asolution of sodium nitrite (800 mg, 11.6 mmol) in water (5.8 mL) wascarefully added dropwise and the mixture was stirred for 1 h at 0° C. KI(1.91 g, 11.6 mmol) was added and the resulting mixture was stirred for3 h at room temperature. The pH of the solution was carefully adjustedto 10 with aqueous sodium hydroxide (3 M) and then extracted with ethylacetate (3×100 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated under reduced pressure to obtain the titlecompound as a white solid (700 mg, 35%).

Compound 256.2.3-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile

Into a 100-mL round-bottom flask, was placed a solution of3-iodo-1H-pyrazole-4-carbonitrile (compound 256.1, 5.00 g, 22.8 mmol) intetrahydrofuran (10 mL). The solution was cooled to 0° C. undernitrogen, then sodium hydride (1.1 g, 27.4 mmol, 60% dispersion inmineral oil) was added in portions. The resulting mixture was stirred at0° C. for 30 min, then (2-(chloromethoxy)ethyl)trimethylsilane (6.05 mL,34.2 mmol) was added to the reaction. The resulting mixture was stirredfor overnight at room temperature, then carefully quenched withwater/ice (30 mL). The aqueous phase was extracted with ethyl acetate(2×100 mL) and the combined organic layers were dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified by asilica gel chromatography with ethyl acetate/petroleum ether (20:1) aseluent to obtain the title compound as a colorless oil (7.2 g, 90%).

Compound 256.3. Methyl3-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-methylbenzoate

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile(compound 256.2, 2.73 g, 7.82 mmol, 1.00 equiv) in dioxane (30 mL).Methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(2.59 g, 9.38 mmol), Pd(dppf)Cl₂ (570 mg, 0.78 mmol), and a solution ofpotassium carbonate (3.24 g, 23.4 mmol) in water (3 mL) were added tothe reaction. The resulting mixture was stirred overnight at 90° C.,then cooled and diluted with EtOAc (500 mL). The resulting mixture waswashed with brine (2×100 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue was purified by a silica gelchromatography with ethyl acetate/petroleum ether (40:1) as eluent toobtained the title compound as a yellow oil (1.9 g, 65%).

Compound 256.4. Methyl 3-(4-cyano-1H-pyrazol-5-yl)-4-methylbenzoate

Into a 50-mL round-bottom flask, was placed a solution of methyl3-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-4-methylbenzoate(compound 256.3, 1.9 g, 5.11 mmol) in triethylsilane (4 mL) andtrifluoroacetic acid (8 mL). The resulting solution was stirred for 4 hat room temperature, then concentrated under reduced pressure. The pH ofthe residue was carefully adjusted to 7-8 with aqueous sodiumbicarbonate (sat.), then the aqueous phase was extracted with ethylacetate (2×100 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(20/1) as eluent to obtain the title compound as a white solid (600 mg,49%).

Compound 256.5. 3-(4-Cyano-1H-pyrazol-5-yl)-4-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244.7, except methyl 3-(4-cyano-1H-pyrazol-5-yl)-4-methylbenzoate(compound 256.4) was used in place of methyl3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6).

Compound 256.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-1H-pyrazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 3-(4-cyano-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound256.5) was used in place of3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7). m/z(ES+) 368 (M+H⁺).

Compound 257.1. 3-Oxobutanenitrile

Into a 250-mL round-bottom flask, which was purged and maintained withan inert atmosphere of nitrogen, was carefully placed(Z)-3-aminobut-2-enenitrile (20.0 g, 244 mmol) and aqueous hydrogenchloride (6 M) (80 mL). The mixture was stirred for 3 h at 80° C., thenthe solids were removed by filtration. The filtrate was extracted withethyl acetate (3×100 mL) and the combined organic extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure to obtain thetitle compound as a yellow solid (10 g, 49%).

Compound 257.2. (Z)-2-(Ethoxymethylene)-3-oxobutanenitrile

Into a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of 3-oxobutanenitrile(compound 257.1, 16.0 g, 193 mmol) in acetic anhydride (48 mL). Triethylorthoformate (96 mL, 577 mmol) was added and the reaction was stirredfor 2 h at 130° C., then concentrated under reduced pressure to obtainthe title compound as a red solid (10 g, 37%).

Compound 257.3. 3-Methyl-1H-pyrazole-4-carbonitrile

Into a 50-mL round-bottom flask, was placed a solution of(Z)-2-(ethoxymethylene)-3-oxobutanenitrile (compound 257.2, 5.00 g, 35.9mmol) in ethanol (10 mL). The solution was cooled to 0° C., thenhydrazine monohydrate (2.09 mL, 43.1 mmol) was added and the reactionwas stirred for 1 h at 10° C. The reaction was diluted with water (10mL) and then extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by a silica gel column withethyl acetate/petroleum ether (1:10) as eluent to obtain the titlecompound as a yellow solid (2.0 g, 52%).

Compound 257.4. 5-Iodo-3-methyl-1H-pyrazole-4-carbonitrile

Into a 10-mL sealed tube, was placed a solution of3-methyl-1H-pyrazole-4-carbonitrile (compound 257.3, 2.0 g, 18.7 mmol)in DCE (6 mL). NIS (4.20 g, 18.7 mmol) was added to the reaction and themixture was irradiated with microwave radiation for 1 h at 150° C. Thereaction was cooled, then carefully quenched with aqueous Na₂S₂O₃ (sat.,20 mL). The mixture was partitioned and the aqueous layer was extractedwith ethyl acetate (100 mL). The combined organic layers were washedwith brine (5×30 mL), dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith ethyl acetate/petroleum ether (1:10) as eluent to obtain the titlecompound as a yellow solid (900 mg, 21%).

Compound 257.5. 3-(4-Cyano-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound256.5, except 5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (compound257.4) was used in place 3-iodo-1H-pyrazole-4-carbonitrile (compound256.1).

Compound 257.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-3-methyl-1H-pyrazole-4-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 3-(4-cyano-3-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid(compound 257.5) was used in place of3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7). m/z(ES+) 382 (M+H⁺).

Compound 258.1. Ethyl 5-iodo-4-methyl-1H-pyrazole-3-carboxylate

Into a 250-mL round-bottom flask, was placed a solution of ethyl4-methyl-1H-pyrazole-3-carboxylate (600 mg, 3.89 mmol) inN,N-dimethylformamide (20 mL). NIS (2.2 g, 9.78 mmol) was added and theresulting mixture was stirred for 6 h at 50° C., then quenched withwater (10 mL). The mixture was extracted with ethyl acetate (3×40 mL)and the combined organic extracts were washed with aqueous Na₂S₂O₃(sat., 2×30 mL) and brine (2×20 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by asilica gel chromatography with ethyl acetate/petroleum ether (1:10) aseluent to obtain the title compound as a white solid (800 mg, 73%).

Compound 258.2. 5-Iodo-4-methyl-1H-pyrazole-3-carboxamide

Into a 100-mL round-bottom flask, was placed a solution of ethyl5-iodo-4-methyl-1H-pyrazole-3-carboxylate (compound 258.1, 500 mg, 1.79mmol) in methanol (5 mL). Then ammonium hydroxide (15 mL, 25% aq.) wasadded and the resulting solution was stirred overnight at 60° C. Themixture was concentrated under reduced pressure to obtain the titlecompound as a white solid (400 mg, 89%).

Compound 258.3. 5-Iodo-4-methyl-1H-pyrazole-3-carbonitrile

Into a 100-mL round-bottom flask, was placed a solution of5-iodo-4-methyl-1H-pyrazole-3-carboxamide (compound 258.2, 800 mg, 3.19mmol) in dichloromethane (10 mL). The solution was cooled to 0° C., thentrifluoroacetic anhydride (1.32 mL, 9.5 mmol) and triethylamine (3.16mL, 22.7 mmol) were each added carefully drop-wise. The mixture wasstirred for 2 h at 0° C., then the pH was carefully adjusted to 7-8 withaqueous sodium bicarbonate (10%). The aqueous phase was extracted withethyl acetate (2×40 mL) and the combined organic layers were washed with2×10 mL of brine (2×10 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue was purified by a silica gelchromatography with ethyl acetate/petroleum ether (1:10) as eluent toobtain the title compound as a white solid (280 mg, 38%).

Compound 258.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-pyrazole-3-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 5-iodo-4-methyl-1H-pyrazole-3-carbonitrile (compound 258.3)was used in place of 3-iodo-4-methoxy-1H-pyrazole (compound 244.5). m/z(ES+) 382 (M+H⁺).

Compound 259.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-1H-pyrazole-3-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound258, except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 396 (M+H⁺).

Compound 260.1. Methyl 5-nitro-1H-pyrazole-3-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of5-nitro-1H-pyrazole-3-carboxylic acid (3.0 g, 19.1 mmol) in methanol (50mL). Sulfuric acid (3 mL) was carefully added and the resulting solutionwas stirred overnight at 80° C., then concentrated under reducedpressure. The pH of the solution was carefully adjusted to 7 withaqueous sodium bicarbonate (sat.), then extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with brine (3×50mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure toobtain the title compound as a yellow solid (2.3 g, 70%).

Compound 260.2. Methyl 5-amino-1H-pyrazole-3-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of methyl5-nitro-1H-pyrazole-3-carboxylate (compound 260.1, 2.5 g, 14.6 mmol) inmethanol (10 mL). The system was purged with nitrogen, thenpalladium/carbon (10 wt % Pd, 0.8 g) was added. The system was chargedwith hydrogen (1 atm) and the mixture was stirred overnight at roomtemperature. The system was purged with nitrogen, then the solids wereremoved by filtration. The filtrate was concentrated under reducedpressure to obtain the title compound as an off-white solid (1.5 g,73%).

Compound 260.3. Methyl 5-iodo-1H-pyrazole-3-carboxylate

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof methyl-5-amino-1H-pyrazole-3-carboxylate (compound 260.2, 1.0 g, 7.1mmol) in a carefully prepared solution of sulfuric acid (15 mL) intowater (30 mL)(Caution: addition of sulfuric acid to water isexothermic). The solution was cooled to 0° C., then a solution of NaNO2(0.53 g, 7.7 mmol) in water (5 mL) was added drop-wise. The resultingmixture was stirred for 2 h at 0° C., then a solution of KI (1.4 g, 8.4mmol) in water (5 mL) was added drop-wise at 0° C. The resulting mixturewas stirred overnight at room temperature, then the pH of the mixturewas carefully adjusted to 7 with aqueous sodium bicarbonate (sat.). Themixture was extracted with ethyl acetate (3×50 mL) and the combinedorganic extracts were washed with brine (3×50 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by a silica gel chromatography with ethyl acetate/petroleumether (1:5) as eluent to obtain the title compound as a yellow solid(0.6 g, 30%).

Compound 260.4. 5-Iodo-1H-pyrazole-3-carboxamide

Into a 100-mL round-bottom flask, was placed a solution of methyl5-iodo-1H-pyrazole-3-carboxylate (compound 260.3, 900 mg, 3.57 mmol) inmethanol (5 mL). Ammonia (25% aq.) (15 mL) was added and the resultingsolution was stirred overnight at 60° C., then cooled and concentratedunder reduced pressure to obtain the title compound as a white solid(0.8 g, 95%).

Compound 260.5. 5-Iodo-1H-pyrazole-3-carbonitrile

Into a 100-mL round-bottom flask, was placed a solution of5-iodo-1H-pyrazole-3-carboxamide (compound 260.4, 1.00 g, 4.22 mmol) indichloromethane (10 mL). The solution was cooled to 0° C., thentrifluoroacetic anhydride (1.8 mL, 12.9 mmol) and triethylamine (4.11mL, 29.5 mmol) were added carefully drop-wise. The mixture was stirredfor 2 h at 0° C., then the pH was carefully adjusted to 7-8 with aqueoussodium bicarbonate (10%). The aqueous phase was extracted with ethylacetate (3×30 mL) and the combined organic layers were washed with brine(2×20 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography withethyl acetate/petroleum ether (1:10) as eluent to obtain the titlecompound as a light yellow solid (180 mg, 19%).

Compound 260.6. 4-Chloro-5-iodo-1H-pyrazole-3-carbonitrile

Into a 50-mL round-bottom flask, was placed a solution of5-iodo-1H-pyrazole-3-carbonitrile (compound 260.5, 100 mg, 0.46 mmol) inN,N-dimethylformamide (10 mL). NCS (61.6 mg, 0.46 mmol) was added andthe resulting mixture was stirred for 2 h at 50° C., then quenched withwater (10 mL). The mixture was extracted with ethyl acetate (3×10 mL)and the combined organic extracts were washed with brine (3×10 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column with ethyl acetate/petroleumether (1:2) as eluent to obtain the title compound as a yellow oil (100mg, 86%).

Compound 260.4-Chloro-5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-1H-pyrazole-3-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-chloro-5-iodo-1H-pyrazole-3-carbonitrile (compound 260.6)was used in place of 3-iodo-4-methoxy-1H-pyrazole (compound 244.5). m/z(ES+) 402 (M+H⁺).

Compound 261.1. (E)-4-Ethoxy-1,1,1-trifluoro-3-methylbut-3-en-2-one

Into a 50-mL 3-neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solutiontrifluoroacetic anhydride (3.31 mL, 23.8 mmol) and diethyl ether (20mL). The solution was cooled to −10° C., then a solution mix of(E)-1-ethoxyprop-1-ene (2.82 mL, 25.5 mmol) and pyridine (1.94 mL, 24.0mmol) was added drop-wise at −10° C. The resulting solution was stirredovernight at room temperature, then diluted with diethyl ether (50 mL).The solids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was diluted with water (100 mL) andextracted with DCM (3×50 mL). The combined organic extracts were washedwith aq HCl (0.1 M, 3×100 mL) and water (100 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure to obtain the titlecompound as a colorless oil (2.6 g, 60%).

Compound 261.2. 4-Methyl-3-(trifluoromethyl)-1H-pyrazole

Into a 100-mL round-bottom flask, was placed(E)-4-ethoxy-1,1,1-trifluoro-3-methylbut-3-en-2-one (compound 261.1, 2.6g, 14.3 mmol) in EtOH (20 mL). Hydrazine hydrate (1.8 mL, 38 mmol) wasadded and the resulting solution was stirred for 2 h at 80° C. Thereaction was concentrated under reduced pressure to obtain the titlecompound as a yellow oil (2 g, crude).

Compound 261.4-(1-(2,4-Dimethyl-5-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-methyl-3-(trifluoromethyl)-1H-pyrazole (compound 261.2)was used in place 4-methoxy-1H-pyrazole (compound 244.4) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 439 (M+H⁺).

Compound 262.1. (Z)-4-(Dimethylamino)-3-(trifluoromethyl)but-3-en-2-one

Into a 100-mL round-bottom flask, was placed 4,4,4-trifluorobutan-2-one(1.7 mL, 15.86 mmol, 1.00 equiv) in toluene (45 mL).1,1-Dimethoxy-N,N-dimethylmethanamine (4.21 mL, 31.7 mmol) was added andthe resulting solution was stirred for 4 h at 100° C., then concentratedunder reduced pressure to obtain the title compound as yellow oil (2.0g, crude).

Compound 262.2. 3-Methyl-4-(trifluoromethyl)-1H-pyrazole

Into a 50-mL round-bottom flask, was placed a solution of(Z)-4-(dimethylamino)-3-(trifluoromethyl)but-3-en-2-one (compound 262.1,2.0 g, 11.0 mmol) in ethanol (30 mL). Hydrazine hydrate (3.7 mL, 77mmol) was added and the resulting solution was stirred overnight at 75°C., then cooled and concentrated under reduced pressure. The residue waspurified by a silica gel chromatography with ethyl acetate/petroleumether (1:2) as eluent to obtain the title compound as a white solid (1.0g, 61%).

Compound 262.4-(1-(2,4-Dimethyl-5-(3-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 3-methyl-4-(trifluoromethyl)-1H-pyrazole (compound 262.2)was used in place 4-methoxy-1H-pyrazole (compound 244.4) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 439 (M+H⁺).

Compound 263.1. N-Methoxy-N-methyltetrahydrofuran-3-carboxamide

Into a 250-mL round-bottom flask, was placed a solution oftetrahydrofuran-3-carboxylic acid (10 g, 86.1 mmol) in dichloromethane(200 mL). EDC-HCl (18.2 g, 94.9 mmol), N,O-dimethylhydroxylaminehydrochloride (10 g, 103 mmol) and triethylamine (24.0 mL, 172 mmol)were added and the resulting mixture was stirred overnight at roomtemperature. The mixture was diluted with DCM (50 mL) and washed withaqueous HCl (1 M, 3×10 mL), sodium bicarbonate (sat., 2×30 mL) and brine(3×20 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure to obtain the title compound aslight yellow oil (6.71 g, 49%).

Compound 263.2. 1-(Tetrahydrofuran-3-yl)propan-1-one

Into a 250-mL 3-neck round-bottom flask, was placed a solution ofN-methoxy-N-methyltetrahydrofuran-3-carboxamide (compound 263.1, 6.71 g,42.2 mmol) in tetrahydrofuran (100 mL). The system was purged withnitrogen, then cooled to 0° C. Ethylmagnesium bromide (3M in diethylether, 17 mL, 51 mmol) was added drop-wise at 0° C. over 30 min. Theresulting solution was stirred overnight at 40° C., then cooled andcarefully quenched with aqueous HCl (1M, 10 mL). The resulting mixturewas concentrated under reduced pressure and the residue was diluted withwater (10 mL). The mixture was extracted with ethyl acetate (3×30 mL)and the combined organic extracts were washed with brine (2×10 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure.Obtained the title compound as a light yellow oil (4.5 g, 83%).

Compound 263.3. 2-Methyl-3-oxo-3-(tetrahydrofuran-3-yl)propanal

Into a 100-mL round-bottom flask, was placed1-(tetrahydrofuran-3-yl)propan-1-one (compound 263.2, 2.5 g, 19.5 mmol),sodium methoxide (1.4 g, 25.9 mmol) and ethyl formate (20 mL). Themixture was stirred overnight at room temperature, then concentratedunder reduced pressure. The residue was purified by a silica gel columnchromatography with ethyl acetate/petroleum ether (1:20 to 1:5) aseluent to obtain the title compound as a yellow solid (2.0 g, 66%).

Compound 263.4. 4-Methyl-5-(tetrahydrofuran-3-yl)-1H-pyrazole

Into a 100-mL round-bottom flask, was placed a solution of2-methyl-3-oxo-3-(tetrahydrofuran-3-yl)propanal (compound 263.3, 3.00 g,19.2 mmol) in ethanol (25 mL). Hydrazine hydrate (1.16 mL, 24 mmol) wasadded and the resulting solution was stirred for 3 h at 80° C. Theresulting mixture was concentrated under reduced pressure to obtain thetitle compound as a colorless oil (3.5 g, crude).

Compound 263.4-(1-(4-Methyl-3-(4-methyl-3-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-methyl-5-(tetrahydrofuran-3-yl)-1H-pyrazole (compound263.4) was used in place of 4-methoxy-1H-pyrazole (compound 244.4). m/z(ES+) 427 (M+H⁺).

Compound 264.1. 1-Cyclopropylpropan-1-one

Into a 250-mL 3-neck round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed cyclopropanecarbonitrile (20.0g, 22.0 mL, 298 mmol) in diethyl ether (100 mL). The solution was cooledto 10° C., then ethylmagnesium bromide (3 M in diethyl ether, 109 mL,327 mmol) was added drop-wise over 10 min. The resulting solution wasstirred overnight at 40° C., then cooled and carefully quenched withaqueous NH₄Cl (sat., 100 mL). The layers were partitioned and theaqueous phase was extracted ethyl acetate (3×200 mL). The combinedorganic layers were washed with brine (3×200 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude product waspurified by distillation under reduced pressure (50 mm Hg) and thefraction collected at 50° C. was the title compound (11 g, 38%).

Compound 264.4-(1-(3-(3-Cyclopropyl-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound263, except 1-cyclopropylpropan-1-one (compound 264.1) was used in placeof 1-(tetrahydrofuran-3-yl)propan-1-one (compound 263.2). m/z (ES+) 397(M+H)⁺.

Compound 265.4-(1-(5-(3-Cyclopropyl-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound263, except 1-cyclopropylpropan-1-one (compound 264.1) was used in placeof 1-(tetrahydrofuran-3-yl)propan-1-one (compound 263.2) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 411 (M+H⁺).

Compound 266.1. 2-Cyclopropyl-3-oxobutanenitrile

Into a 100-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of argon, was placed a solution of2-cyclopropylacetonitrile (3.70 mL, 40.1 mmol) in THF (20 mL). Thesolution was cooled to −78° C., then LDA (2 M in THF, 30 mL, 60 mmol)was added drop-wise and the mixture was stirred for 1 h at −78° C. Asolution of acetic anhydride (4.54 mL, 48.0 mmol) in tetrahydrofuran (10mL) was added drop-wise at −78° C. The mixture was stirred for 1 h at15° C., then carefully quenched with citric acid (10% aq, 200 mL). Themixture was extracted with diethyl ether (2×70 mL) and the combinedorganic extracts were washed with brine (50 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure to obtain the titlecompound, which was used in the next step without purification.

Compound 266.2. 4-Cyclopropyl-3-methyl-1H-pyrazol-5-amine

Into a 250-mL round-bottom flask, was placed a solution of2-cyclopropyl-3-oxobutanenitrile (compound 266.1, 4.0 g, 32.5 mmol) inethanol (18 mL). AcOH (3 mL) and hydrazine hydrate (3.15 mL, 65 mmol)were added and the reaction was stirred overnight at 80° C. The reactionwas cooled, then the pH was carefully adjusted to 9 with NaHCO₃ (aq.sat.). The mixture was diluted with water, then extracted with ethylacetate (6×60 mL) and the combined organic extracts were washed withbrine (80 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure to obtain the title compound as a brown oil (4.17 g, crude),which was used in the next step without purification.

Compound 266.3. 4-Cyclopropyl-5-iodo-3-methyl-1H-pyrazole

Into a 250-mL 3-neck round-bottom flask, was placed a solution of4-cyclopropyl-3-methyl-1H-pyrazol-5-amine (compound 266.2, 3.8 g, 27.7mmol) in ACN (40 mL). The solution was cooled to 0° C., then AcOH (4.8mL, 83 mmol) was carefully added followed by a drop-wise addition of asolution of KI (11.5 g, 69.3 mmol) in water (40 mL). The mixture wasstirred for 10 min at 0° C., then tert-butyl nitrite (8.24 mL, 69.3mmol) in ACN (40 mL) was added drop-wise. The resulting mixture wasstirred at 0° C. for 10 min, then at room temperature for 2 h. The pH ofthe reaction was carefully adjusted to 8 with sodium bicarbonate (aq.sat.) and extracted with ethyl acetate (4×50 mL). The combined organicextracts were washed with Na₂S₂O₃ (aq. sat., 80 mL) and brine (2×80 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by a silica gel chromatography with ethylacetate/petroleum ether (1:2) as eluent to obtain the title compound asa yellow solid (1.71 g, 25%).

Compound 266.4-(1-(5-(4-Cyclopropyl-3-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-cyclopropyl-5-iodo-3-methyl-1H-pyrazole (compound 266.3.)was used in place of 3-iodo-4-methoxy-1H-pyrazole (compound 244.5) andmethyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 411 (M+H)⁺.

Compound 267.1. Methyl 4-cyclopropyl-2-methylbenzoate

To a solution of methyl 4-bromo-2-methylbenzoate (5.00 g, 20.7 mmol,1.00 equiv, 95%) in a mixture of toluene and H₂O (20 mL/1 mL) were addedpotassium carbonate (6.10 g, 44.1 mmol, 2.00 equiv), cyclopropylboronicacid (2.30 g, 26.8 mmol, 1.20 equiv), Pd(dppf)Cl₂ (900 mg, 1.23 mmol,0.05 equiv), and Pd(OAc)₂ (250 mg, 1.12 mmol, 0.05 equiv). The reactionmixture was purged with nitrogen and stirred at 80° C. overnight. Aftercooling to room temperature, the mixture was then concentrated underreduced pressure. The resulting residue was purified via silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:50) aseluent to yield 2.68 g (61%) of methyl 4-cyclopropyl-2-methylbenzoate asa colorless oil.

Compound 267.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate

To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 267.1,2.68 g, 13.4 mmol, 1.00 equiv, 95%) in AcOH (50 mL) were added NaIO₄(1.51 g, 7.08 mmol, 0.50 equiv), I₂ (3.58 g, 14.1 mmol, 1.00 equiv), andsulfuric acid (201 mg, 2.01 mmol, 0.15 equiv, 98%). The reaction mixturewas stirred at 110° C. overnight. After cooling to ambient temperature,100 mL of water was added. The resulting mixture was diluted with 100 mLof ethyl acetate, then washed with 3×30 mL of Na₂S₂O₃ (aq., sat.) and1×30 mL of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified via silica gel column chromatography with ethylacetate/petroleum ether (1/50) as eluent to yield 2.00 g (45%) of methyl4-cyclopropyl-5-iodo-2-methylbenzoate as a colorless oil.

Compound 267.3. Methyl4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound5.4, except methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound267.2) was used in place of methyl 3-iodo-4-methylbenzoate (compound5.3).

Compound 267.4-(1-(4-Cyclopropyl-5-(3,4-dimethyl-1H-pyrazol-5-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 59,except methyl4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 267.3) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 411 (M+H)⁺.

Compound 268.1. Ethyl 1-benzyl-4-methyl-1H-pyrazole-3-carboxylate

Into a 100-mL 3-neck round-bottom flask, was placed a solution of ethyl4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 6.5 mmol) in tetrahydrofuran(20 mL). The solution was cooled to 0° C., then sodium hydride (360 mg,9.00 mmol, 60% dispersion in mineral oil) was added in portions and themixture was stirred for 20 min. Benzyl bromide (904 μL, 7.60 mmol) wasadded at 0° C., then the resulting mixture was stirred for 1.5 h at roomtemperature. The reaction was carefully quenched with by drop-wiseaddition of water (35 mL) and the mixture was extracted with ethylacetate (3×100 mL). The combined organic extracts were washed with ofbrine (3×100 mL), dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by a silica gelchromatography with ethyl acetate/petroleum ether (1:20-1:2) as eluentto obtain the title compound as a yellow solid (1.0 g, 63%).

Compound 268.2. (1-Benzyl-4-methyl-1H-pyrazol-3-yl)methanol

Into a 100-mL 3-neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution of ethyl1-benzyl-4-methyl-1H-pyrazole-3-carboxylate (compound 268.1, 2.3 g, 9.42mmol) in THF (30 mL). The solution was cooled to 0° C., then LiAlH₄ (360mg, 9.49 mmol, 1.00 equiv) was carefully added in portions. Theresulting mixture was stirred for 1 h at room temperature, thencarefully quenched by drop-wise addition of water (400 μL), then aqueousNaOH (10%, 400 μL), followed by additional water (1.2 mL). The solidswere removed by filtration and the filtrate was dried (Na₂SO₄), filteredand concentrated under reduced pressure to obtain the title compound asa yellow oil (1.7 g, 89%).

Compound 268.3. 1-Benzyl-3-(methoxymethyl)-4-methyl-1H-pyrazole

Into a 250-mL 3-neck round-bottom flask, was placed a solution of(1-benzyl-4-methyl-1H-pyrazol-3-yl)methanol (compound 268.2, 1.7 g, 8.4mmol) in THF (50 mL). The solution was cooled to 0° C., then sodiumhydride (470 mg, 11.8 mmol, 60% dispersion in mineral oil) was added inportions at 0° C., and then the mixture was stirred for 20 min.Iodomethane (750 μL, 12 mmol) was added at 0° C., then the resultingmixture was stirred for 2 h at room temperature. The reaction wascarefully quenched by drop-wise addition of water (30 mL) and themixture was extracted with ethyl acetate (3×100 mL). The combinedorganic extracts were washed with brine (3×100 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by a silica gel chromatography with ethyl acetate/petroleumether (1:10) as eluent to obtain the title compound as a yellow oil (1.5g, 83%).

Compound 268.4. 3-(Methoxymethyl)-4-methyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed a solution of1-benzyl-3-(methoxymethyl)-4-methyl-1H-pyrazole (compound 268.3, 700 mg,3.24 mmol) in methanol (10 mL). The system was purged with nitrogen,then Pd(OH)₂/C (70 mg, 20 wt %) and aqueous HCl (2 M, 0.3 mL) werecarefully added. The system was then charged with hydrogen (1 atm) andthe resulting mixture was stirred for 2 days at room temperature. Thesystem was purged with nitrogen, then the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. ThepH of the residue was adjusted to 7 with aqueous sodium bicarbonate(sat.) and extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with brine (2×30 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure to obtain the title compound as ayellow oil (500 mg, crude).

Compound 268.4-(1-(5-(3-(Methoxymethyl)-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 3-(methoxymethyl)-4-methyl-1H-pyrazole (compound 268.4) wasused in place 4-methoxy-1H-pyrazole (compound 244.4) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) m/z (ES+) 415 (M+H)⁺.

Compound 269.4-(1-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 3-iodobenzoic acid was used in place of 3-iodo-4-methylbenzoicacid and 4-bromo-3,5-dimethyl-1H-pyrazole was used in place of5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 357 (M+H)⁺.

The compounds in TABLE 12 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 263.

TABLE 12 m/z (ES+) Cpd Name Structure (M + H)⁺ 3304-(1-(2,4-dimethyl-5-(4- methyl-3- (tetrahydrofuran-3-yl)- 1H-pyrazol-5-yl)benzoyl)azetidin-3- yl)benzonitrile

441 331 4-(1-(2,4-dimethyl-5-(4- methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5- yl)benzoyl)azetidin-3- yl)benzonitrile

455 274 4-(1-(2,4-dimethyl-5-(4- methyl-3- (tetrahydrofuran-2-yl)-1H-pyrazol-5- yl)benzoyl)azetidin-3- yl)benzonitrile

441

The compounds in TABLE 13 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 268.

TABLE 13 m/z (ES+) Cpd Name Structure (M + H)⁺ 275 4-(1-(5-(3-((cyclopropylmethoxy) methyl)-4-methyl-1H- pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin- 3-yl)benzonitrile

455 286 4-(1-(5-(3- (hydroxymethyl)-4- methyl-1H-pyrazol-5-yl)- 2,4-dimethylbenzoyl)azetidin- 3-yl)benzonitrile

401 309 4-(1-(2,4-dimethyl-5-(4- methyl-3-((oxetan-3- yloxy(methyl)-1H-pyrazol-5- yl)benzoyl)azetidin-3- yl)benzonitrile

457 356 (5-(5-(3-(4- cyanophenyl)azetidine-1- carbonyl)-2,4-dimethylphenyl)-4- methyl-1H-pyrazol-3- yl)methyl acetate

443 350 4-(1-(5-(3- (isopropoxymethyl)-4- methyl-1H-pyrazol-5-yl)- 2,4-dimethylbenzoyl)azetidin- 3-yl)benzonitrile

443 312 4-(1-(2,4-dimethyl-5-(4- methyl-3-((2,2,2-trifluoroethoxy)methyl)- 1H-pyrazol-5- yl)benzoyl)azetidin-3-yl)benzonitrile

483

The compounds in TABLE 14 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 249.

TABLE 14 m/z (ES+) Cpd Name Structure (M + H)⁺ 277 4-(1-(5-(3-(cyclopropylmethoxy)-4- methyl-1H-pyrazol-5-yl)- 2,4-dimethylbenzoyl)azetidin- 3-yl)benzonitrile

441 276 4-(1-(5-(3-(2- methoxyethoxy)-4- methyl-1H-pyrazol-5-yl)- 2,4-dimethylbenzoyl)azetidin- 3-yl)benzonitrile

445

Compound 279.4-(1-(5-(3-Chloro-4-methoxy-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds244 and 250. m/z (ES+) 421 (M+H)⁺.

Compound 281.1. 3-(Methoxymethyl)-1H-pyrazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound268.4, except methyl 1H-pyrazole-3-carboxylate was used instead ofmethyl 4-methyl-1H-pyrazole-3-carboxylate.

Compound 281.2. 4-Chloro-3-(methoxymethyl)-1H-pyrazole

To a solution of 3-(methoxymethyl)-1H-pyrazole (compound 281.1, 200 mg,1.78 mmol) in chloroform (20 mL) was added NCS (237 mg, 1.77 mmol). Thereaction mixture was stirred overnight at room temperature, thenquenched with 20 mL of H₂O. The aqueous phase was extracted with 3×50 mLof ethyl acetate. The combined organic layers were washed with 3×20 mLof brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith EtOAc:PE (1:2) as the eluent to furnish 50 mg (19%) of the titlecompound as a white solid.

Compound 281.3. Methyl5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244.6, except 4-chloro-3-(methoxymethyl)-1H-pyrazole (compound 281.2)was used instead of 4-methoxy-1H-pyrazole (compound 244.4).

Compound 281.4-(1-(5-(4-Chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except methyl5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate(compound 281.3) was used instead of methyl3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6). m/z(ES+) 435 (M+H)⁺.

Compound 304.1.5-(3-(Bromomethyl)-4-chloro-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid

A mixture of methyl5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate(compound 281.3, 20 mg, 0.06 mmol) and HBr-HOAc (5 mL) was stirredovernight at 80° C., then concentrated under reduced pressure to yield20 mg (90%) of the title compound as a yellow oil.

Compound 304.2.5-(4-Chloro-3-(hydroxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid

A mixture of5-(3-(bromomethyl)-4-chloro-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid(compound 304.1, 200 mg, 0.58 mmol) and NaHCO₃ (0.3 M, 10 mL) wasstirred for 30 min at room temperature, then concentrated under reducedpressure. This resulted in 200 mg (crude) of the title compound as awhite solid.

Compound 304.4-(1-(5-(4-Chloro-3-(hydroxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except5-(4-chloro-3-(hydroxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid(compound 304.2) was used instead of3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7). m/z(ES+) 421 (M+H)⁺.

Compound 280.1.4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.82 g, 30.0mmol) in tetrahydrofuran (80 mL). This was followed by the addition ofNaH (70%) (2.05 g, 85.4 mmol) in portions at 0° C. To this was addedSEMCl (6.4 mL, 36.1 mmol) dropwise. The reaction mixture was stirredovernight at room temperature, then quenched with 50 mL of NH₄Cl (sat).The aqueous phase was extracted with 2×100 mL of ethyl acetate and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. This resulted in 7 g (72%) of thetitle compound as colorless oil.

Compound 280.2. 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(compound 280.1, 9.7 g, 30.0 mmol) in THF (100 mL) was added 2M sodiumhydroxide (aq.) (30 mL) dropwise. To this was added H₂O₂ (30%) (22.7 mL)dropwise at 0° C. The reaction mixture was stirred for 2 h at roomtemperature, then quenched with 50 mL of water. The aqueous phase wasextracted with 2×150 mL of ethyl acetate and the combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure. This resulted in 4.3 g (67%) of the title compound as a whitesolid.

Compound 280.3.4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol(compound 280.2, 2.14 g, 10.0 mmol) in tetrahydrofuran (50 mL) was addedCs₂CO₃ (6.5 g, 20.0 mmol) in portions. To this was added CH₃I (1.25 mL,20.0 mmol) dropwise. The reaction mixture was stirred for 3 h at roomtemperature, then concentrated under reduced pressure. The resultingresidue was dissolved in 100 mL of EtOAc. The solids were filtered offand the filtrate was concentrated under reduced pressure. This resultedin 2.1 g (92%) of the title compound as a colorless oil.

Compound 280.4.4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylicacid

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (compound280.3, 4.6 g, 20.0 mmol) in tetrahydrofuran (50 mL). This was followedby the addition of n-BuLi (2.5 M in hexane) (10 mL) dropwise at −78° C.The reaction mixture was stirred for 1 h at −60° C. To this was addedCO₂(solid) (5 g) with stirring at −78° C. The reaction mixture waswarmed slowly to room temperature and was stirred for 1 h, then quenchedwith 10 mL of NH₄Cl (sat.). The pH value of the solution was adjusted to5-6 with HCl (1 M). The aqueous phase was extracted with 2×100 mL ofethyl acetate and the combined organic layers were dried over sodiumsulfate and concentrated under reduced pressure. This resulted in 5 g(92%) of the title compound as a white solid.

Compound 280.5.4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide

To a solution of4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylicacid (compound 280.4, 5 g, 18.4 mmol) in N,N-dimethylformamide (50 mL)were added EDC-HCl (7 g, 36.5 mmol), NH₄Cl (1.97 g, 36.8 mmol) and4-dimethylaminopyridine (8.95 g, 73.3 mmol). The mixture was stirred for2 h at room temperature, then warmed to 50° C. for 3 h. The reactionmixture was quenched with 30 mL of NH₄Cl (sat). The aqueous phase wasextracted with 2×100 mL of ethyl acetate. The combined organic layerswere washed with 3×100 mL of NH₄Cl (sat), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:5) as the eluent to furnish 1.3 g (26%) of the title compound.

Compound 280.6.4-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile

To a solution of4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide(compound 280.5, 1.08 g, 4.0 mmol) in toluene (25 mL) was added POCl₃(1.86 mL, 20.0 mmol) dropwise at 0° C. The mixture was stirred for 2 hat 50° C., then quenched with 30 mL of sodium bicarbonate (sat.). Theaqueous phase was extracted with 2×100 mL of ethyl acetate and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1:6) as theeluent to yield 500 mg (49%) of the title compound as a white solid.

Compound 280.7. 4-Methoxy-1H-pyrazole-3-carbonitrile

A mixture of4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile(compound 280.6, 500 mg, 1.97 mmol) and trifluoroacetic acid (10 mL) inTES (5 mL) was stirred for 2 h at room temperature, then concentratedunder reduced pressure. The residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1:2) as the eluent tofurnish 210 mg (86%) of the title compound as a white solid.

Compound 280.8. 5-Iodo-4-methoxy-1H-pyrazole-3-carbonitrile

To a solution of 4-methoxy-1H-pyrazole-3-carbonitrile (compound 280.7,200 mg, 1.62 mmol) in N,N-dimethylformamide (15 mL) was added NIS (549mg, 2.44 mmol). The reaction mixture was stirred for 2 h at 70° C., thenquenched with 20 mL of Na₂S₂O₃ (sat.). The aqueous phase was extractedwith 2×50 mL of ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:6) as the eluent to furnish 330 mg (82%) ofthe title compound as a white solid.

Compound 280.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-4-methoxy-1H-pyrazole-3-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 5-iodo-4-methoxy-1H-pyrazole-3-carbonitrile (compound 280.8)was used instead of 4-chloro-5-iodo-1H-pyrazole-3-carbonitrile (compound260.6) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 412 (M+H⁺).

Compound 294.1.(E)-3-(Dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one

To a sealed tube were added 1-(tetrahydro-2H-pyran-4-yl)ethanone (3.00g, 23.4 mmol) and DMF-DMA (6.2 mL, 46.8 mmol). The reaction mixture washeated at 100° C. overnight. The resulting mixture was concentratedunder reduced pressure to afford 4.00 g (crude) of the title compound aslight yellow oil.

Compound 294.2. 3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazole

To a solution of(E)-3-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one(compound 294.1, 4.3 g, 23.4 mmol) in ethanol (20 mL) was addedNH₂NH₂.H₂O (1.41 g, 28.2 mmol). The reaction mixture was stirred for 3 hat 80° C. The resulting mixture was concentrated under reduced pressureto yield 4.45 g (crude) of the title compound as a light yellow solid.

Compound 294.3. 4-Chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

To a solution of 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound294.2, 3.5 g, 23.0 mmol) in tetrahydrofuran (20 mL) was added NCS (3.4g, 25.4 mmol). The reaction mixture was stirred overnight at 40° C. Theresulting mixture was concentrated under reduced pressure. This resultedin 4.75 g (crude) of the title compound as a light yellow solid.

Compound 294.4. 4-Chloro-5-iodo-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

To a solution of 4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole(compound 294.3, 3.00 g, 16.1 mmol) in N,N-dimethylformamide (20 mL) wasadded NIS (7.26 g, 32.3 mmol). The reaction mixture was stirredovernight at 80° C. The reaction mixture was diluted with 50 mL Na₂S₂O₃(sat.). The aqueous phase was extracted with 3×100 mL of ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1/8-1/5) as theeluent to furnish 4.05 g (81%) of the title compound as a white solid.

Compound 294.4-(1-(5-(4-Chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-chloro-5-iodo-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole(compound 294.4) was used instead of was used in place4-methoxy-1H-pyrazole (compound 244.4) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 475 (M+H)⁺.

Compound 293.1. 4-Chloro-3-cyclopropyl-5-iodo-1H-pyrazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound294.4, except 1-cyclopropylethanone was used instead of1-(tetrahydro-2H-pyran-4-yl)ethanone.

Compound 293.4-(1-(5-(4-Chloro-3-cyclopropyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound294, except 4-chloro-3-cyclopropyl-5-iodo-1H-pyrazole (compound 293.1)was used instead of4-chloro-5-iodo-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound294.4). m/z (ES+) 431 (M+H)⁺.

Compound 305.1. N,N,4-Trimethyl-1H-pyrazole-1-sulfonamide

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of 4-methyl-1H-pyrazole(10.4 g, 127.2 mmol) in CH₂Cl₂ (200 mL). N,N-dimethylsulfamoyl chloride(17.14 mL, 167.1 mmol) and triethylamine (35 mL, 251.1 mmol) were addedto the reaction. The reaction mixture was stirred for 30 min at 0° C. ina water/ice bath and then stirred overnight at room temperature. Thereaction was quenched with NaHCO₃ (sat.) (40 mL) and the aqueous phasewas extracted with 3×200 mL of EtOAc. The combined organic phase wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography withethyl acetate/hexanes (1:6) as the eluent to afford the title compound(22.2 g, 92%) as a light yellow oil.

Compound 305.2.3-(2-Hydroxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide

Into a 50-mL three-neck round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution ofN,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.1, 1.19 g, 6.26mmol) in THF (24 mL). n-BuLi (3 mL, 7.5 mmol, 2.5 M in hexanes) wasadded to the reaction dropwise at −78° C. The resulting mixture wasstirred for 30 min at −78° C. This was followed by the addition of asolution of oxirane (5.6 mL, 113.51 mmol) in THF (4 mL) at −78° C. Thereaction mixture was then brought to room temperature and stirred for 3h. The reaction was quenched with 10 mL of NH₄Cl (sat.) and the aqueousphase was extracted with 3×50 mL of EtOAc. The combined organic layerswere dried over Na₂SO₄. The solvent was removed to give the crudeproduct which was purified by silica gel chromatography withhexanes/EtOAc (3:1) as the eluent to furnish 636 mg (44%) of the titlecompound as light yellow oil.

Compound 305.3.3-(2-Methoxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of3-(2-hydroxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound305.2, 636 mg, 2.73 mmol) in THF (10 mL). Sodium hydride (131 mg, 60% inmineral oil, 3.27 mmol) was added at 0° C. and stirred for 30 min at 0°C. This was followed by the addition of CH₃I (204 μL, 3.28 mmol). Thereaction mixture was stirred for 3 h at room temperature. The reactionwas quenched with 10 mL of NH₄Cl (sat.) and the aqueous phase wasextracted with 3×50 mL of EtOAc. The combined organic phases were driedover Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure to give the crude product which was purified by silicagel chromatography with hexanes/EtOAc (15:1-8:1) as the eluent to give452 mg (67%) of the title compound as a yellow oil.

Compound 305.4. 3-(2-Methoxyethyl)-4-methyl-1H-pyrazole

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of3-(2-methoxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound305.3, 440 mg, 1.78 mmol) in dioxane (10 mL). HCl (10 mL, 6 M, 30 mmol)was added to the reaction mixture. The reaction mixture was stirred for1 h at 85° C., then cooled to room temperature and carefully neutralizedwith NaHCO₃ aq (sat.) to pH-8. The aqueous phase was extracted with 3×50mL of EtOAc and the combined organic layers were dried over Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressureto give the crude product which was used in the next step withoutfurther purification.

Compound 305.5. 5-Iodo-3-(2-methoxyethyl)-4-methyl-1H-pyrazole

Into a 50-mL round-bottom flask (1 atm) purged and maintained with aninert atmosphere of nitrogen, was placed a solution of3-(2-methoxyethyl)-4-methyl-1H-pyrazole (compound 305.4, 249 mg, 1.78mmol) in N,N-dimethylformamide (10 mL). NIS (482 mg, 2.14 mmol, 1.20equiv) was added to the reaction. The reaction mixture was stirred for 2h at 60° C., then cooled and quenched with 5 mL of NH₄Cl (sat.). Theaqueous phase was extracted with 3×30 mL of EtOAc and the combinedorganic layers were dried over Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure to give the crude product whichwas purified by silica gel chromatography with hexanes/EtOAc (5:1) asthe eluent to yield 328 mg (69% over two steps) of the title compound asa brown oil.

Compound 305.4-(1-(5-(3-(2-Methoxyethyl)-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 5-iodo-3-(2-methoxyethyl)-4-methyl-1H-pyrazole (compound305.5) was used instead of 3-iodo-4-methoxy-1H-pyrazole (compound 244.5)and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 429 (M+H)⁺.

Compound 307.1. 3-(2-Methoxyethyl)-1H-pyrazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound305.4, except 1H-pyrazole was used instead of 4-methyl-1H-pyrazole.

Compound 307.2. 4-Chloro-5-iodo-3-(2-methoxyethyl)-1H-pyrazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound294.4, except 3-(2-methoxyethyl)-1H-pyrazole (compound 307.1) was usedinstead of 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound 294.2).

Compound 307.4-(1-(5-(4-Chloro-3-(2-methoxyethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 4-chloro-5-iodo-3-(2-methoxyethyl)-1H-pyrazole (compound307.2) was used instead of 3-iodo-4-methoxy-1H-pyrazole (compound 244.5)and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 449 (M+H)⁺.

Compound 357.1. (Z)-Methyl 2-((dimethylamino)methylene)-3-oxobutanoate

Into a 250-mL round-bottom flask, was placed methyl 3-oxobutanoate (10.8g, 92.6 mmol) and (dimethoxymethyl)dimethylamine (12.7 mL, 95.3 mmol).The resulting solution was stirred for 2.5 h at 80° C., thenconcentrated under reduced pressure to yield 14.5 g (crude) of the titlecompound as a red solid.

Compound 357.2. Methyl 1-benzyl-3-methyl-1H-pyrazole-4-carboxylate

To a solution of (Z)-methyl 2-((dimethylamino)methylene)-3-oxobutanoate(15.8 g, 92.5 mmol) in ethanol (50 mL) was added 1-benzylhydrazinedihydrochloride (18 g, 92.3 mmol). The resulting solution was stirredfor 3.5 h at 80° C., then concentrated under reduced pressure. Theresidue was dissolved in 200 mL of ethyl acetate. The organic layer waswashed with 1×40 mL of water and 2×40 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:4) as the eluent to furnish 12.4 g (58%) of the title compound as ayellow solid.

Compound 357.4-(1-(5-(4-(Methoxymethyl)-3-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound268, except methyl 1-benzyl-3-methyl-1H-pyrazole-4-carboxylate (compound357.2) was used instead of ethyl1-benzyl-4-methyl-1H-pyrazole-3-carboxylate (compound 268.1). m/z (ES+)415 (M+H)⁺.

Compound 314.1. 1-Benzyl-3-methyl-1H-pyrazole

To a solution of 3-methyl-1H-pyrazole (5.00 g, 60.9 mmol) intetrahydrofuran (30 mL) was added sodium hydride (60%) (4.88 g, 203mmol) in portions at 0° C. and stirred for 30 min under nitrogen. To theabove mixture was added benzyl bromide (8.7 mL, 73.1 mmol). The reactionmixture was stirred for 1 h at room temperature, then carefully quenchedwith 150 mL of water. The aqueous phase was extracted with 3×30 mL ofEtOAc. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford 5.66 g (54%)of the title compound as light yellow oil.

Compound 314.2. 1-Benzyl-3-methyl-1H-pyrazole-4-carbaldehyde

To a solution of 1-benzyl-3-methyl-1H-pyrazole (compound 314.1, 1.00 g,5.81 mmol) in N,N-dimethylformamide (3 mL) was added POCl₃ (493 μL, 5.28mmol) dropwise. The reaction mixture was stirred for 3 h at 90° C. undernitrogen. The reaction mixture was diluted with 50 mL of H₂O. The pH ofthe solution was adjusted to 7 with sodium hydroxide (2 M). The aqueousphase was extracted with 3×20 mL of ethyl acetate and the combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder reduced pressure to yield 1.42 g (crude) of the title compound asa brown oil.

Compound 314.3.1-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanol

To a solution of 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde (compound314.2, 1.20 g, 5.99 mmol) in tetrahydrofuran (15 mL) was added CF₃SiMe₃(1.33 mL, 9.01 mmol) and TBAF (0.11 mL, 0.11 mmol, 1M solution in THF).The mixture was stirred for 10 min at room temperature under nitrogen.This was followed by the addition of aqueous HCl (6 M) (1 mL). Thereaction mixture was stirred for another 10 min at room temperature,then diluted with 50 mL of H₂O. The aqueous phase was extracted with3×20 mL of ethyl acetate and the combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1/5-1/2) as the eluent to furnish 1.15 g (71%)of the title compound as a light yellow solid.

Compound 314.4.O-(1-(1-Benzyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)O-phenylcarbonothioate

To a solution of1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanol (compound314.3, 1.15 g, 4.26 mmol) in toluene (15 mL) were added4-dimethylaminopyridine (1.47 g, 12.0 mmol) and phenylchloromethanethioate (1.04 g, 6.02 mmol). The reaction mixture wasstirred for 1 h at 60° C. under nitrogen, then concentrated underreduced pressure. The residue was purified by silica gel chromatographywith ethyl acetate/petroleum ether (1/15) as the eluent to yield 1.34 g(77%) of the title compound as a light yellow oil.

Compound 314.5. 1-Benzyl-3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole

To a solution ofO-(1-(1-benzyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)O-phenylcarbonothioate (compound 314.4, 1.34 g, 3.30 mmol) in toluene (20 mL)was added Bn₃SnH (3.84 mL, 13.2 mmol), AIBN (320 mg, 1.95 mmol). Thereaction mixture was stirred for 1 h at 80° C. under nitrogen, thenconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1:20) as theeluent to furnish 650 mg (78%) of the title compound as a colorless oil.

Compound 314.6. 3-Methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole

To a solution of 1-benzyl-3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole(compound 314.5, 700 mg, 2.75 mmol) in methanol (10 mL) was addedpalladium on carbon (700 mg, 10 wt. %) and HCl (4 M) (3 mL). Thereaction mixture was hydrogenated for 48 h at room temperature under 1atmosphere of hydrogen. The solids were removed via filtration. Thefiltrate was evaporated under reduced pressure and diluted with 50 mL ofwater. The pH of the solution was adjusted to 7 with NaOH (2 M). Theaqueous phase was extracted with 5×20 mL of ethyl acetate and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford 230 mg (51%) of the titlecompound as a light yellow oil.

Compound 314.4-(1-(2,4-Dimethyl-5-(3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound244, except 3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole (compound314.6) was used instead of 4-methoxy-1H-pyrazole (compound 244.4) andmethyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 453 (M+H)⁺.

Compound 313.1. 1-Benzyl-4-methyl-1H-pyrazole-3-carbaldehyde

To a solution of (1-benzyl-4-methyl-1H-pyrazol-3-yl)methanol (compound268.2, 3 g, 14.8 mmol) in dichloromethane (100 mL) was added PDC (11.3g, 30.1 mmol), molecular sieves (3 g) and NaOAc (300 mg) were added tothe reaction mixture. The reaction mixture was stirred for 4 h at roomtemperature. The solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by asilica gel chromatography with ethyl acetate/petroleum ether (1/10) asthe eluent to yield 1 g (34%) of the title compound as a colorless oil.

Compound 313.4-(1-(2,4-Dimethyl-5-(4-methyl-3-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound314, except 1-benzyl-4-methyl-1H-pyrazole-3-carbaldehyde (compound313.1) was used instead of 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde(compound 314.2). m/z (ES+) 453 (M+H)⁺.

Compound 374.1. N,N,4-Trimethyl-1H-pyrazole-3-carboxamide

To a mixture of 4-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 7.93mmol), HOBT (1.07 g, 7.93 mmol) and EDCI (2.27 g, 11.89 mmol) in DMF (10mL) was added DIEA (2.74 mL, 15.86 mmol). After the mixture was stirredat room temperature for 16 hours, dimethylamine (2M in THF, 11.89 mL,23.79 mmol) was added. The mixture was stirred at room temperature for 3hours, then partitioned between EtOAc (300 mL) and water (30 mL). Theorganics was washed with brine (3×30 mL) and the combined aqueousmaterial was back extracted with EtOAc (2×50 mL). All organic extractswere combined, dried (MgSO₄), filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(5% MeOH in CH₂Cl₂) to obtain the title compound as a brown oil (1.1 g,92%). m/z (ES+) 154 (M+H)⁺.

Compound 374.2. 5-Iodo-N,N,4-trimethyl-1H-pyrazole-3-carboxamide

To a solution of N,N,4-trimethyl-1H-pyrazole-3-carboxamide (compound374.1, 0.98 g, 6.40 mmol) in CH₃CN (10 mL) was added NIS (1.59 g, 7.04mmol). The mixture was stirred at room temperature for 16 hours thenquenched with sat. Na₂SO₃ solution (5 mL). The mixture was partitionedbetween EtOAc (200 mL) and water (30 mL). The EtOAc layer was washedwith brine (30 mL), dried (MgSO₄) and concentrated. The residue waspurified with column chromatography (50% EtOAc in hexanes to 100% EtOAc)to give the product as a brown solid (1.79 g, 100%). m/z (ES+) 280(M+H)⁺.

Compound 374.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-N,N,4-trimethyl-1H-pyrazole-3-carboxamide

The title compound was prepared using the standard chemicalmanipulations and procedures similar to those used for the preparationof compound 5, except 5-iodo-N,N,4-trimethyl-1H-pyrazole-3-carboxamide(compound 374.2) was used instead of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5) and methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 442 (M+H)⁺.

Compound 375.5-(5-(3-Fluoro-3-(p-tolyl)azetidine-1-carbonyl)-2,4-dimethylphenyl)-N,N,4-trimethyl-1H-pyrazole-3-carboxamide

The title compound was prepared using the standard chemicalmanipulations and procedures similar to those used for the preparationof compound 5, except 5-iodo-N,N,4-trimethyl-1H-pyrazole-3-carboxamide(compound 374.2) was used instead of 5-iodo-2,4-dimethyl-1H-imidazole(compound 5.5), methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride(compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrilehydrochloride (compound 5.2). m/z (ES+) 460 (M+H)⁺.

Compound 329.(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-methylphenyl)(4-(4-methoxyphenyl)piperidin-1-yl)methanone

The title compound was prepared using the standard chemicalmanipulations and procedures similar to those used for the preparationof compound 5, except 4-(4-methoxyphenyl)piperidine hydrochloric acidsalt was used instead of 4-(azetidin-3-yl)benzonitrile hydrochloride(compound 5.2). m/z (ES+) 404 (M+H)⁺.

Compound 284.1. Methyl3-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound219.4, except methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used instead of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1).

Compound 284.2.3-(2-(Hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid

Into a 100-mL round-bottom flask, was placed methyl3-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoate(compound 284.1, 2 g, 6.36 mmol), HBr (40% in AcOH) (50 mL). Thereaction mixture was stirred for 12 h at 80° C. The crude product (100mL) was purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): mobile phase, CH₃CN:H₂O=1:1; Detector, UV 254 nm toyield 1 g (52%) of the title compound as a light yellow solid.

Compound 284.4-(1-(3-(2-(Hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except3-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 284.2) was used in place of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7). mz (ES+) 441 (M+H)⁺.

The compounds in TABLE 15 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 284.

TABLE 15 m/z (ES+) Cpd Name Structure (M + H)⁺ 285 4-(3-fluoro-1-(3-(2-(hydroxymethyl)-4- (trifluoromethyl)-1H- imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile

459 352 4-(1-(3-(2-(2- hydroxyethyl)-4- (trifluoromethyl)-1H-imidazol-5-yl)-4- methylbenzoyl)azetidin- 3-yl)benzonitrile

455 362 4-(1-(3-(2-(2- methoxyethyl)-4- (trifluoromethyl)-1H-imidazol-5-yl)-4- methylbenzoyl)azetidin- 3-yl)benzonitrile

468 360 4-(1-(3-(2- (methoxymethyl)-4- (trifluoromethyl)-1H-imidazol-5-yl)-4- methylbenzoyl)azetidin- 3-yl)benzonitrile

455

Compound 287.1.5-Iodo-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound202.2, except tetrahydro-2H-pyran-4-carbaldehyde was used instead of3-methlyoxetane-3-carbaldehyde.

Compound 287.2. Methyl4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound202.4, except5-iodo-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole(compound 287.1) was used instead of5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound202.3).

Compound 287.3.4-Methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoicacid

A solution of methyl4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoate(compound 287.2, 50 mg, 0.14 mmol) in HCl (6 M) (2 mL) was stirred for 5h at 80° C., then concentrated under reduced pressure. This resulted 200mg (crude) of the title compound as a brown solid which was used in thenext step without further purification.

Compound 287.4-(1-(4-Methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound202, except4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoicacid (compound 287.3) was used instead of3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 202.5). m/z (ES+) 495 (M+H)⁺.

The compounds in TABLE 16 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 287 and 202.

TABLE 16 m/z (ES+) Cpd Name Structure (M + H)⁺ 288 4-(1-(4-methyl-3-(2-(4-methyltetrahydro- 2H-pyran-4-yl)-4- (trifluoromethyl)-1H- imidazol-5-yl)benzoyl)azetidin-3- yl)benzonitrile

509 290 4-(1-(4-methyl-3-(2- (1-methylpiperidin-4-yl)-4-(trifluoromethyl)- 1H-imidazol-5- yl)benzoyl)azetidin-3-yl)benzonitrile

508 291 methyl 4-(5-(5-(3-(4- cyanophenyl)azetidine- 1-carbonyl)-2-methylphenyl)-4- (trifluoromethyl)-1H- imidazol-2- yl)piperidine-1-carboxylate

552 292 4-(1-(4-methyl-3-(2- (1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)- 1H-imidazol-5- yl)benzoyl)azetidin-3-yl)benzonitrile

494 289 4-(1-(4-methyl-3-(2- (3-methyloxetan-3-yl)- 4-(trifluoromethyl)-1H-imidazol-5- yl)benzoyl)azetidin-3- yl)benzonitrile

481

The compounds in TABLE 17 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 230 and 231.

TABLE 17 m/z (ES+) Cpd Name Structure (M + H)⁺ 3534-(1-(3-(4-chloro-2-(2- hydroxyethyl)-1H- imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile

421 354 4-(1-(3-(4-chloro-2-(2- hydroxyethyl)-1H- imidazol-5-yl)-4-methylbenzoyl)-3- fluoroazetidin-3- yl)benzonitrile

439 359 4-(1-(3-(4-chloro-2- (methoxymethyl)-1H- imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile

421 361 4-(1-(3-(4-chloro-2-(2- methoxyethyl)-1H- imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile

435

Compound 283.(4-Chloro-5-(5-(3-(4-cyanophenyl)-3-fluoroazetidine-1-carbonyl)-2-methylphenyl)-1H-imidazol-2-yl)methylacetate

Into a 50-mL round-bottom flask, was placed a solution of4-(1-(3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 29, 40 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL).Triethylamine (14 μL, 0.10 mmol) was added to the reaction at 0° C.,followed by acetic anhydride (10 μL, 0.10 mmol). The reaction mixturewas stirred for 2 h at room temperature, then diluted with 10 mL ofethyl acetate. The organic layer was washed with 3×5 mL of brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude product (35 mg) was purified by Prep-HPLC with the followingconditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um,19*100 mm; mobile phase, WATER WITH 0.05% TFA and MeCN (10% MeCN up to70% in 6 min, up to 95% in 1 min, down to 10% in 1 min); Detector,Waters 2489 254 & 220 nm. This resulted in 15 mg (34%) of the titlecompound as a white solid. m/z (ES+) 467 (M+H)⁺.

The compounds in TABLE 18 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 185, 192 and 194.

TABLE 18 m/z (ES+) Cpd Name Structure (M + H)⁺ 344 methyl 4-(5-(5-(3-(4-cyanophenyl)azetidine- 1-carbonyl)-2- methylphenyl)-4-methyl-1H-imidazol-2- yl)-4- hydroxypiperidine-1- carboxylate

514 345 methyl 4-(5-(5-(3-(4- cyanophenyl) azetidine-1-carbonyl)-2-methylphenyl)-4- methyl-1H-imidazol-2- yl)-4- methoxypiperidine-1-carboxylate

528

The compounds in TABLE 19 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 185 and 241.

TABLE 19 m/z (ES+) Cpd Name Structure (M + H)⁺ 3464-(1-(3-(4-chloro-2-(4- methyltetrahydro-2H- pyran-4-yl)-1H-imidazol-5-yl)-4- methylbenzoyl)azetidin- 3-yl)benzonitrile

475 347 4-(1-(3-(4-chloro-2-(4- methyltetrahydro-2H- pyran-4-yl)-1H-imidazol-5-yl)-4- methylbenzoyl)-3- fluoroazetidin-3-yl) benzonitrile

494 348 methyl 4-(4-chloro-5-(5- (3-(4-cyanophenyl)azetidine-1-carbonyl)-2- methylphenyl)-1H- imidazol-2-yl)-4-methylpiperidine-1- carboxylate

532

The compounds in TABLE 20 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 14.

TABLE 20 m/z (ES+) Cpd Name Structure (M + H)⁺ 3584-(3-fluoro-1-(4-methyl-3-(4- methyl-2-(trifluoromethyl)- 1H-imidazol-5-yl)benzoyl)azetidin-3- yl)benzonitrile

443 366 4-(1-(2,4-dimethyl-5-(4- methyl-2-(trifluoromethyl)-1H-imidazol-5- yl)benzoyl)azetidin-3- yl)benzonitrile

439 367 4-(1-(2,4-dimethyl-5-(4- methyl-2-(trifluoromethyl)-1H-imidazol-5-yl)benzoyl)-3- fluoroazetidin-3- yl)benzonitrile

457 363 4-(1-(3-(4-ethyl-2- (trifluoromethyl)-1H- imidazol-5-yl)-4-methylbenzoyl)azetidin-3- yl)benzonitrile

439 364 4-(1-(3-(4-(methoxymethyl)- 2-(trifluoromethyl)-1H-imidazol-5-yl)-4- methylbenzoyl)azetidin-3- yl)benzonitrile

455 365 4-(1-(3-(4-cyclopropyl-2- (trifluoromethyl)-1H-imidazol-5-yl)-4- methylbenzoyl)azetidin-3- yl)benzonitrile

451

The compounds in TABLE 21 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compound 218.

TABLE 21 m/z (ES+) Cpd Name Structure (M + H)⁺ 3684-(3-fluoro-1-(4-methyl-3-(2- methyl-4-(trifluoromethyl)- 1H-imidazol-5-yl)benzoyl)azetidin-3- yl)benzonitrile

443 369 4-(1-(2,4-dimethyl-5-(2- methyl-4-(trifluoromethyl)-1H-imidazol-5- yl)benzoyl)azetidin-3- yl)benzonitrile

439 370 4-(1-(2,4-dimethyl-5-(2- methyl-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoyl)-3- fluoroazetidin-3- yl)benzonitrile

457

Compound 282.1. N,N,2-Trimethyl-1H-imidazole-1-sulfonamide

To a solution of 2-methyl-1H-imidazole (10 g, 121.8 mmol) indichloromethane (100 mL) was added N,N-dimethylsulfamoyl chloride (14.4mL, 133.7 mmol) and triethylamine (34 mL, 244.1 mmol). The reactionmixture was stirred overnight at room temperature, then quenched with 10mL of water and extracted with 1×50 mL of DCM. The organic layer waswashed with 2×20 mL of brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1:2) as theeluent to furnish 20 g (87%) of the title compound as a yellow oil.

Compound 282.2.4-(2-Hydroxyethyl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamide

Into a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was placed a solutionof N,N,2-trimethyl-1H-imidazole-1-sulfonamide (compound 282.1, 6.4 g,33.8 mmol) in tetrahydrofuran (50 mL). This was followed by the additionof n-BuLi (2.5M in hexane) (16.3 mL, 40.6 mmol) dropwise with stirringat −78° C. The reaction mixture was stirred for 1 h at −78° C. Oxirane(12.1 mL, 242.89 mmol) was added dropwise at −30° C. The reactionmixture was stirred for 2 h at room temperature, then quenched with 10mL of water. The aqueous phase was extracted with 3×30 mL of ethylacetate. The combined organic layers were washed with 3×20 mL of brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography withEtOAc:MeOH (40:1) as the eluent to yield 3.4 g (43%) of the titlecompound as a white solid.

Compound 282.3. 2-(2-Methyl-1H-imidazol-4-yl)ethanol

To a solution of4-(2-hydroxyethyl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamide (compound282.2, 1 g, 4.29 mmol) in 1,4-dioxane (30 mL) was added HCl (6 M, 30mL). The reaction mixture was stirred for 4 h at 85° C., thenconcentrated under reduced pressure. The pH of the solution was adjustedto 7-8 with NaHCO₃ (sat.). The resulting mixture was concentrated underreduced pressure to afford 3 g (crude) of the title compound as a whitesolid.

Compound 282.4-(1-(3-(4-(2-Hydroxyethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 2-(2-methyl-1H-imidazol-4-yl)ethanol (compound 282.3) was usedinstead of 2,4-dimethyl-1H-imidazole. m/z (ES+) 401 (M+H)⁺.

Compound 295.1.4-(1-(3-(4-Formyl-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 5-iodo-2-methyl-1H-imidazole-4-carbaldehyde (compound 236.1) wasused instead of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).

Compound 295.4-(1-(3-(4-(Difluoromethyl)-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

To a solution of4-(1-(3-(4-formyl-2-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 295.1, 100 mg, 0.26 mmol) in dichloromethane (10 mL) was addedDAST (103 μL, 0.78 mmol) at −70° C. The reaction mixture was stirred for5 h at room temperature. The pH of the solution was adjusted to 7 withsodium bicarbonate (sat.). The aqueous phase was extracted with 20 mL ofdichloromethane and the combined organic layers were washed with 3×10 mLof brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith ethyl acetate/petroleum ether (1:20-1:2) as the eluent. The crudeproduct (100 mg) was purified by Prep-HPLC with the following conditions(Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um, 19*100 mm;mobile phase, WATER WITH 0.05% TFA and ACN (16.0% up to 30.0% in 7 min,up to 95.0% in 1 min, down to 16.0% in 1 min); Detector, Waters 2489 254& 220 nm. This resulted in 48.7 mg (36%) of the title compound as awhite solid. m/z (ES+) 407 (M+H)⁺.

Compound 300.1. Ethyl 4-methoxycyclohexanecarboxylate

Into a 100-mL round-bottom flask, was placed a solution of ethyl4-hydroxycyclohexane-1-carboxylate (1 g, 5.81 mmol) in tetrahydrofuran(20 mL). Sodium hydride (349 mg, 8.72 mmol, 60%) was added to thereaction at 0° C. in portions, then stirred for 20 min. This wasfollowed by the addition of CH₃I (865 μL, 11.6 mmol) at 0° C. Thereaction mixture was stirred overnight at room temperature, quenchedwith 6 mL of brine and extracted with 3×40 mL of ether. The combinedorganic layers were washed with 2×20 mL of brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford 800 mg(74%) of the title compound as a colorless oil.

Compound 300.2. 4-Methoxycyclohexanecarbaldehyde

Into a 100-mL 3-neck round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of ethyl4-methoxycyclohexane-1-carboxylate (1.3 g, 6.98 mmol) in dichloromethane(30 mL). This was followed by the addition of DIBAL-H (1 M in hexanes)(9 mL, 9 mmol) dropwise at −78° C. The reaction mixture was stirred for3 h at −78° C., then quenched with 10 mL of NH₄Cl (sat.). The aqueousphase was extracted with 3×50 mL of ethyl acetate. The combined organiclayers were washed with 3×50 mL of brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. This resulted in 1 g(crude) of the title compound as a colorless oil.

Compound 300.2. methyl3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound160.3, except 4-methoxycyclohexanecarbaldehyde (compound 300.2) was usedinstead of cyclopropanecarbaldehyde and methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used instead of except methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1).

Compound 300.3.3-(2-(4-Methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid

Into a 50-mL round-bottom flask, was placed a solution of methyl3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate(compound 300.2, 150 mg, 0.44 mmol) in methanol (4 mL). A solution ofNaOH (70 mg, 1.75 mmol) in water (2 mL) was added to the reaction. Thereaction mixture was stirred for 3 h at 50° C., then concentrated underreduced pressure. The reaction mixture was diluted with 2 mL of water.The pH of the solution was adjusted to 1 with HCl (2 M) and concentratedunder reduced pressure. This resulted in 240 mg (crude) of the titlecompound as a light yellow solid.

Compounds 300.A and 300.B.4-(1-(3-(2-(4-Methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 50-mL round-bottom flask, was placed a solution of3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 300.3, 140 mg, 0.43 mmol) in N,N-dimethylformamide (3mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 82.8 mg,0.43 mmol), HBTU (242.6 mg, 0.64 mmol) and DIEA (228 μL, 1.28 mmol) wereadded to the reaction. The reaction mixture was stirred for 1 overnightat room temperature, then diluted with 60 mL of EtOAc. The organic layerwas washed with 3×20 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The crude product (150 mg) waspurified by Prep-HPLC with the following conditions (Prep-HPLC-020):Column, SunFire Prep C18 OBD Column, 5 μm, 19*100 mm; mobile phase, and(20.0% up to 27.0% in 10 min, up to 95.0% in 3 min, down to 20.0% in 1min); Detector, Waters 2489 254 & 220 nm. This resulted in 18.4 mg (9%)of compound 300.A as a white solid and 59.2 mg (30%) of compound 300.Bas an off-white solid. m/z (ES+) 469 (M+H)⁺.

Compound 332.1.3-(2-(4-Hydroxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid

A solution of methyl3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate(compound 300.2, 300 mg, 0.88 mmol) in HI (45% in water) (3 mL) wasstirred for 2 h at 60° C., then concentrated under reduced pressure.This resulted in 500 mg (crude) of the title compound as brown oil whichwas used into the next step without further purification.

Compound 332.4-(3-(3-(2-(4-Hydroxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)cyclobutyl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except3-(2-(4-hydroxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoicacid (compound 332.1) was used instead of3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid hydrochloride(compound 5.7). m/z (ES+) 455 (M+H)⁺.

Compound 355.1.4-(1-(3-(2-Acetyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except 1-(4-methyl-H-imidazol-2-yl)ethanone was used in place of2,4-dimethyl-1H-imidazole.

Compound 355.4-(1-(3-(2-(1,1-Difluoroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-(1-(3-(2-acetyl-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 355.1, 85 mg, 0.21 mmol) in dichloromethane (15 mL). This wasfollowed by the addition of DAST (82 μL, 0.62 mmol). The reactionmixture was stirred for 4 days at room temperature, while adding fifteenadditional equivalent of DAST over 4 days. The reaction was thenquenched by the addition of 10 mL of water. The aqueous phase wasextracted with 3×50 mL of dichloromethane and the combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith ethyl acetate/hexanes (6:1) as the eluent. The crude product (54mg) was purified by Prep-HPLC with the following conditions(Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um, 19*100 mm;mobile phase, WATER WITH 0.05% TFA and MeCN (24.0% MeCN up to 38.0% in 5min, up to 95.0% in 1 min, down to 34.0% in 1 min); Detector, Waters2489 254 & 220 nm. This resulted in 42.8 mg (38%) of the title compound(trifluoroacetic acid salt) as a white solid. m/z (ES+) 421 (M+H)⁺.

Compound 371.1. N,2-Dimethyl-1H-imidazole-4-carboxamide

2-Methyl-1H-imidazole-4-carboxylic acid (378 mg, 3 mmol), EDCI (745 mg,3.9 mmol), HOBt (253 mg, 1.5 mmol), DIEA (1.6 mL, 9 mmol) and methylamine (2M in THF) (3.6 mL, 7.2 mmol) were dissolved in DMF (10 mL) andstirred at room temperature for 16 hours. After removal of DMF, theresidue was dry loaded and purified by flash chromatography (SiO₂; 0-10%methanol in DCM and 1% NH₄OH) to give 280 mg (67%) of the titlecompound. m/z (ES+) 140 (M+H)⁺.

Compound 371.5-(5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-N,2-dimethyl-1H-imidazole-4-carboxamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except N,2-dimethyl-1H-imidazole-4-carboxamide (compound 371.1) was usedinstead of 2,4-dimethyl-1H-imidazole. m/z (ES+) 414 (M+H)⁺.

Compound 349.1. 4,4,4-Trifluoro-2-oxobutanal

To a solution of SeO₂ (4.23 g, 38.1 mmol) in dioxane (25 mL) was addedAcOH/H₂O (1 mL/1 mL). 4,4,4-Trifluorobutan-2-one (3.81 mL, 31.7 mmol)was added dropwise to the above reaction mixture. The resulting solutionwas stirred overnight at 100° C. The solution was used in the next stepwithout any further work-up or purification.

Compound 349.2. 2-Methyl-4-(2,2,2-trifluoroethyl)-1H-imidazole

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159.1, except 4,4,4-trifluoro-2-oxobutanal (compound 349.1) was usedinstead of methylglyoxal.

Compound 349.4-(1-(2,4-Dimethyl-5-(2-methyl-4-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159, except 2-methyl-4-(2,2,2-trifluoroethyl)-1H-imidazole (compound349.2) was used instead of 2-isopropyl-4-methyl-1H-imidazole (compound159.1). m/z (ES+) 453 (M+H)⁺.

Compound 296.4-(1-(4-Methyl-3-(2-methyl-4-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound159, except 2-methyl-4-(2,2,2-trifluoroethyl)-1H-imidazole (compound349.2) was used instead of 2-isopropyl-4-methyl-1H-imidazole (compound159.1) and methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4) was used instead of methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 160.1). m/z (ES+) 439 (M+H)⁺.

Compound 377.1. Methyl4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl4-fluoro-5-iodo-2-methylbenzoate (compound 101.2, 5.04 g, 17.1 mmol) inDMSO (50 mL).4,4,5,5-Tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.23 g, 20.6 mmol), KOAc (5.04 g, 51.4 mmol), Pd(dppf)Cl₂ (2.51 g, 3.43mmol) were added to the reaction. The reaction mixture was stirred for 2h at 90° C., then cooled and diluted with 300 mL of EtOAc. The solidswere filtered off and the filtrate was washed with 3×30 mL of brine(sat.). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1/30) as theeluent to furnish 3.97 g (79%) of the title compound as an off-whitesolid.

Compound 377.2.4-(1-(5-(3,4-Dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 59,except methyl4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 377.1) was used in place of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4). m/z (ES+) 389 (M+H)⁺.

Compound 377.4-(1-(4-(Azetidin-1-yl)-5-(3,4-dimethyl-1H-pyrazol-5-yl)-2-methylbenzoyl)azetidin-3-yl)benzonitrile

Into a 5-mL sealed tube, was placed a solution of4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 377.2, 120 mg, 0.31 mmol) in dioxane (3 mL). Azetidine (833μL, 12.4 mmol) and Cs₂CO₃ (1.01 g, 3.09 mmol) were added to thereaction. The reaction mixture was stirred for 20 h at 120° C., thencooled with a water/ice bath. The resulting solution was diluted with 30mL of EtOAc. The organic layer was washed with 3×20 mL of brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude product (200 mg) was purified by Prep-HPLC with the followingconditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um,19*100 mm; mobile phase, Water with 10 mmol NH₄HCO₃ and MeCN (36.0% MeCNup to 50.0% in 6 min, up to 95.0% in 2 min, down to 36.0% in 1 min);Detector, waters 2489 254 & 220 nm. This resulted in 56 mg (43%) of thetitle compound as a white solid. m/z (ES+) 426 (M+H)⁺.

Compound 376.1. Methyl4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound377.1, except methyl 4-fluoro-3-iodobenzoate (compound 132.1) was usedinstead of methyl 4-fluoro-5-iodo-2-methylbenzoate (compound 101.2).

Compound 376.2.4-(1-(3-(2,4-Dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 5,except methyl4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 376.1) was used instead of methyl4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(compound 5.4).

Compound 376.4-(1-(4-(Azetidin-1-yl)-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound377, except4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)azetidin-3-yl)benzonitrile(compound 376.2) was used instead of4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile(compound 377.2). m/z (ES+) 412 (M+H)⁺.

The compounds in TABLE 22 were prepared using standard chemicalmanipulations and procedures similar to those used for the preparationof compounds 14, 101, 375 and 376.

TABLE 22 m/z (ES+) Cpd Name Structure (M + H)⁺ 3824-(1-(4-(azetidin-1-yl)-3- (4-methyl-2- (trifluoromethyl)-1H-imidazol-5- yl)benzoyl)azetidin-3- yl)benzonitrile

466 383 4-(1-(3-(2,4-dimethyl-1H- imidazol-5-yl)-4-(3- methylazetidin-1-yl)benzoyl)azetidin-3- yl)benzonitrile

426 384 4-(1-(3-(2,4-dimethyl-1H- imidazol-5-yl)-4- (pyrrolidin-1-yl)benzoyl)azetidin-3- yl)benzonitrile

426 385 4-(1-(3-(2,4-dimethyl-1H- imidazol-5-yl)-4-(3-methoxypyrrolidin-1- yl)benzoyl)azetidin-3- yl)benzonitrile

456

Compound 378.4-(1-(4-Chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 50,except 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.2). m/z (ES+) 391 (M+H)⁺.

Compound 379.4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-(trifluoromethyl)benzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 50and 378. m/z (ES+) 425 (M+H)⁺.

Compound 380.4-(1-(3-(2-((cis)-4-methoxycyclohexyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds202, 287, 300A and 300B. m/z (ES+) 523 (M+H)⁺.

Compound 381.4-(1-(3-(2-((trans)-4-methoxycyclohexyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds202, 287, 300A and 300B. m/z (ES+) 523 (M+H)⁺.

The compounds of the present disclosure in TABLE 26 below were, or maybe, prepared using the foregoing procedures, as well as standardchemical manipulations and procedures similar to the foregoingprocedures.

Example 2 Activity of Compound of the Present Disclosure AntiviralActivity

The antiviral activities of the compounds were assessed using the HCV1breplicon system. The replicon was constructed using the ET(luc-ubi-neo/ET) cell line, a Huh7 human hepatoma cell line harboring anHCV replicon with a stable luciferase (Luc) reporter and three cellculture-adaptive mutations (Pietschmann, et al (2002) J. Virol.76:4008-4021). The HCV replicon antiviral evaluation assay examined theeffects of compounds at ten three-fold dilutions. Sub-confluent culturesof the ET line were plated out into 96-well plates that were dedicatedfor the analysis of cell viability (cytotoxicity) or antiviral activityand the next day drugs were added to the appropriate wells. Cells wereprocessed 72 hr later when the cells are still sub-confluent. EC₅₀(concentrations inhibiting the HCV RNA replicon by 50%), CC₅₀(concentration decreasing cell viability by 50%) and SI (selectiveindex: CC₅₀/EC₅₀) values were determined. HCV RNA replicon levels wereassessed using the Bright-Glo™ Luciferase Assay System (Promega) tomeasure replicon-derived Luc activity. The CellTiter-Glo™ LuminescentCell Viability Assay (Promega) was used to estimate cell viability.Inhibition of HCV for selected compounds is disclosed in TABLE 26. Noneof the compounds in TABLE 26 caused material cytotoxicity at the highestconcentrations tested.

FASN Inhibition by Compounds of the Present Disclosure

Determination of FASN Biochemical Activity:

The FASN enzyme was isolated from SKBr3 cells. SKBr3 is a human breastcancer cell-line with high levels of FASN expression. It is estimatedthat FASN comprises about 25% of the cytosolic proteins in this cellline. SKBr3 cells were homogenized in a dounce homogenizer thencentrifuged for 15 minutes at 4° C. to remove particulate matter. Thesupernatant was then analyzed for protein content, diluted to theappropriate concentration, and used to measure FASN activity. Thepresence of FASN was confirmed by western blot analysis. A similarmethod for isolation of FASN from SKBr3 cells is described in Teresa, P.et al. (Clin. Cancer Res. 2009; 15(24), 7608-7615).

FASN activity of the SKBr3 cell extract was determined by measuringeither NADPH oxidation or the amount of thiol-containing coenzyme A(CoA) released during the fatty acid synthase reaction. The dye CPM(7-diethylamino-3-(4′-maleimidyl-phenyl)-4-methylcoumarin) contains athiol reactive group that increases its fluorescence emission onreaction with the sulfhydryl group of CoA. The biochemical activitiesshown in TABLE 26 were determined using the fluorescence measurement ofCoA release via a procedure described in Chung C. C. et al. (Assay andDrug Development Technologies, 2008, 6(3), 361-374).

FASN Inhibitors have Oncology Efficacy

Experimental Procedures

Cell Viability Assay:

For drug treatment, PANC-1 cells were plated in 96-well plates at aconcentration of 1.0×10³ per well in medium (Advanced MEM containing 1%or 10% FBS). Serial 3-fold dilutions of compounds 160, 161, 242, or 164were prepared in DMSO and further diluted 1:10 in Advanced MEM foraddition to the assay solution. 24-hours after cell plating, advancedMEM-diluted compound was added to make a final reaction volume of 100 ulper well. Final drug concentrations in assay wells were 10,000, 3,300,1,100, 370, 123, 41, 14, 5, and 0 nmol/L. Assays were done in triplicateat each drug concentration 10 days after compound addition. The numberof viable cells was measured using the Cell Titer-Glo assay (Promega)according to the manufactures instructions. Luminosity per well wasdetermined and the signal intensity was analyzed versus drugconcentration. For each FASN inhibitor, the concentration of drugresulting in 50% inhibition of the maximum signal was determined, andthis value was reported as the IC₅₀.

Xenograft Tumor Growth Inhibition Efficacy Study:

For xenograft tumor development and drug treatment, female BALB/c-nudemice, 8-9 weeks of age, were inoculated subcutaneously at the rightflank with PANC-1 tumor cells (5×10⁶) in 0.1 ml of PBS. The day of tumorcell inoculation is denoted as day 0. Drug treatment was initiated whenthe mean tumor size reached 149 mm³ (day 15). Drug administration totumor-bearing mice (n=10 per group) was according to the followingregimen: compound 161: 30 or 60 mg/kg once daily (Qd); compound 242: 30or 60 mg/kg once daily (Qd); C75(trans-4-methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid): 30mg/kg once every 5 days (Q5d); gemcitabine 40 mg/kg once every 3 days(Q3d). The administered dose of C75 was lowered to 20 mg/kg once every 5days following the first dose, due to drug-induced weight loss andtoxicity. Mice were assigned into treatment groups using a randomizedblock design based upon their tumor volumes. This ensured that all thegroups were comparable at the start of treatment. Tumor sizes weremeasured twice weekly in two dimensions using a caliper, and the volumeswere expressed in mm³ using the formula: V=0.5 a×b2 where a and b werethe long and short diameters of the tumor, respectively. The study wasterminated 6 hours post the 18^(th) Qd dose on day 32 after tumorinoculation. Tumor growth inhibition (TGI) was calculated as thepercentage of tumor growth, relative to tumor size at the start oftreatment, in drug-treated groups compared to vehicle-treated groups.The Mann-Whitney U test was used to assess statistical significance ofthe mean tumor size between drug and vehicle-treated groups.

Results

FASN Inhibition Inhibits Tumor Cell Growth and Induces Cell Death:

To test for effects of FASN inhibition on tumor cell survival, apancreatic tumor cell line (PANC-1) was treated with multiple FASNinhibitors, and IC₅₀ values were determined from a 9-point dose responsecell viability assay. Cell survival IC₅₀ values were determined 10 daysfollowing addition of FASN inhibitor compounds to the tumor cells (TABLE23). FASN cell survival IC₅₀ values were in agreement with previouslydetermined FASN biochemical and cell-based IC₅₀ values in palmitatesynthesis and HCV replicon assays. Alignment of IC50 values inphenotypic (cell survival) and mechanistic (palmitate synthesis) assaysdemonstrates that tumor cell death induced by FASN inhibitor treatmentis a direct result of FASN inhibition.

TABLE 23 FASN inhibitor in vitro cell assay IC₅₀ values Survival HCVPalmitate FASN PANC-1 HeLa HeLa Biochem. Treatment (nM) (nM) (nM) (nM)Compound 160 16^(a) 7 24 17 Compound 161 112^(a)  34 51 32 Compound 24242^(b) 77 74 42 Compound 164   1.2^(b) 2 27 19 ^(a)Advanced MEM cellmedium with 10% FBS ^(b)Advanced MEM cell medium with 1% FBS

FASN Inhibition Inhibits In Vivo Xenograft Tumor Growth:

To test for the effects of FASN inhibition on in vivo tumor growth,PANC-1 xenograft tumors were inoculated subcutaneously in femaleBALB/c-nude mice. When the xenograft tumors grew to an average of 149mm³ (day 15 following tumor cell inoculation), drug treatment wasinitiated with 3-V Biosciences reversible FASN inhibitors (compound 161or 242) or control compounds (C75 or gemcitabine) to determine tumorgrowth inhibition activity of the different compounds in the PANC-1xenograft tumor model. Drug treatment groups consisted of10-tumor-bearing mice per group. The FASN inhibitors, compounds 161 and242 both demonstrated tumor growth inhibition activity in adose-responsive manner. Compound 161 dosed at 60 mg/kg once daily for 18days resulted in 52% tumor growth inhibition compared to vehicle treatedmice, and compound 242 dosed at 100 mg/kg once daily for 18 daysresulted in 57% tumor growth inhibition compared to vehicle treated mice(TABLES 24 and 25). Once daily 30 mg/kg doses of compounds 161 and 242resulted in 31% and 19% tumor growth inhibition, respectively. C75, theirreversible FASN inhibitor control compound was dosed initially at 30mg/kg once every 5 days; however, toxicity of this compound required adose adjustment to 20 mg/kg once every 5 days. The C75 treatment groupafter 18 days (3 doses) showed 65% tumor growth inhibition. Six of theten mice in the C75 treatment group died from C75-related toxicityduring the 18-day study. Gemcitabine treated PANC-1 tumor-bearing mice(40 mg/kg once every 3 days) showed 96 percent tumor growth inhibition.Tumor growth inhibition induced by compounds 161 and 242, C75, andgemcitabine was statistically significant compared to vehicle treatedmice. The results from this study demonstrate that reversible FASNinhibitors discovered at 3-V Biosciences are well tolerated in PANC-1xenograft tumor-bearing mice, and that once-daily dosing of theinhibitors as a single agent cancer therapeutic is associated withstatistically significant tumor growth inhibition compared to vehicletreated mice. Additional studies to investigate dosing levels,schedules, and in combination with existing standard of carechemotherapies are being pursued.

Tumor Volumes

The tumor sizes of each treatment group at different time points areshown in TABLE 24.

TABLE 24 Mean tumor sizes in the different treatment groups Tumor volume(mm³)^(a) Treatment 15 19 22 26 29 32 Compound 161 (30 mg/kg) 150 ± 13159 ± 10 211 ± 17 297 ± 31 379 ± 53 479 ± 69 Compound 161 (60 mg/kg) 150± 13 178 ± 23 213 ± 32 207 ± 33 261 ± 51 413 ± 83 Compound 242 (30mg/kg) 149 ± 12 219 ± 24 240 ± 18 304 ± 21 394 ± 24 543 ± 38 Compound242 (100 mg/kg) 149 ± 13 157 ± 15 187 ± 22 247 ± 29 300 ± 39 378 ± 59C75 (30/20 mg/kg) 150 ± 15 164 ± 22 156 ± 26 213 ± 43 367 ± 77 403 ± 83Gemcitabine (40 mg/kg) 149 ± 12 144 ± 16 152 ± 14 177 ± 20 172 ± 21 165± 27 Vehicle 1 (0.5% CMC) 148 ± 11 200 ± 23 242 ± 32 423 ± 57 491 ± 57 638 ± 108 Vehicle 2 (20% DMSO, 146 ± 11 212 ± 11 277 ± 18 409 ± 18 474± 24 614 ± 29 80% PBS) Note: ^(a)Mean ± SEM.

Tumor Growth Inhibition

The tumor growth inhibition (TGI) and statistical analysis of eachtreatment group at the study conclusion (day 32) is summarized in TABLE25.

TABLE 25 Antitumor activity of compounds 161 and 242 as a single agentin the treatment of subcutaneous PANC-1 human pancreatic cancerxenograft model TGI vs. P-value TGI vs. P-value Vehicle vs. Vehicle vs.Treatment 1 (%) Vehicle 1 2 (%) Vehicle 2 Compound 161 (30 mg/kg) 310.310 29 0.052 Compound 161 (60 mg/kg) 52 0.188 51 0.014 Compound 242(30 mg/kg) 19 0.950 16 0.244 Compound 242 (100 mg/kg) 57 0.043 56 0.002C75 (30/20 mg/kg) 65 0.024 64 0.002 Gemcitabine (40 mg/kg) 96 <0.001 96<0.001 Vehicle 1 (0.5% CMC) — — — 1.000 Vehicle 2 (20% DMSO, 80% — 1.000— — PBS)

TABLE 26 Compounds of the present disclosure. Hu FASN HCV GT1b StructureCpd IC50 (μM) EC50 (μM)

1 0.024 0.027

2 0.041 0.037

3 0.032 0.068

4 0.053 0.081

5 0.010 0.009

6 0.105 0.086

7 0.006 0.003

8 0.040 0.050

9 0.025 0.030

10 0.027 0.030

11 0.036 0.044

12 0.036 0.160

13 0.006 0.005

14 0.027 0.031

15 0.026 0.022

16 0.018 0.013

17 0.045 0.081

18 0.540

19 0.030 0.042

20 0.165 0.130

21 0.207 0.390

22 1.690 2.220

23 0.029 0.093

24 0.041 0.097

25 0.019

26 0.245

27 0.009 0.005

28 0.048 0.011

29 0.024 0.009

30 0.016 0.013

31 0.011 0.003

32 0.012 0.003

33 0.080

34 0.048

35 2.870 2.780

36 9.190

37 0.032 0.032

38 0.104 0.640

39 0.420 0.980

40 0.620 1.700

41 50.000

42 0.032 0.115

43 0.012 0.004

44 0.007 0.003

45 0.009 0.002

46 0.005 0.004

47 0.007 0.003

48 0.009 0.004

49 0.009 0.003

50 0.145 0.250

51 0.019 0.051

52 0.046 0.280

53 0.033 0.100

54 0.020 0.033

55 0.086 0.320

56 0.021 0.032

57 0.097

58 0.102 0.310

59 0.033 0.063

60 0.110 0.360

61 0.310

62 0.650 0.760

63 1.180 6.170

64 1.550 1.940

65 0.050 0.096

66 2.370 15.000

67 2.490

68 0.150 0.240

69 0.018 0.016

70 0.205 0.680

71 0.300 0.710

72 0.420 2.220

73 1.000 2.570

74 0.460 0.730

75 0.073 0.111

76 0.069 0.245

77 0.125 0.170

78 3.670 5.420

79 0.059 0.150

80 0.057 0.295

81 0.054 0.200

82 0.020 0.036

83 0.062 0.089

84 0.112 0.540

85 0.057

86 0.086 0.850

87 0.040 0.029

88 0.021 0.009

89 0.049 0.087

90 0.071 0.165

91 0.140 0.140

92 0.140 0.230

93 0.034

94 0.029 0.630

95 0.030 0.008

96 0.270

97 0.190

98 0.240 0.960

99 0.045

100 0.055 0.070

101 0.530

102 0.890

103 0.135

104 0.070 0.270

105 0.070 0.030

106 50.000 20.000

107 5.580 20.000

108 2.250 15.000

109 0.280 0.350

110 11.020 20.000

111 0.230 1.980

112 0.840 1.490

113 0.145 0.270

114 0.200 0.450

115 0.320 1.210

116 50.000 20.000

117 0.980 3.330

118 0.680 3.180

119 4.480 10.000

120 1.300 10.000

121 0.030 0.240

122 3.440

123 3.710

124 0.140 0.230

125 0.110 0.110

126 1.130

127 3.270

128 0.098 0.120

129 1.210 2.150

130 0.082 3.200

131 0.185 2.200

132 0.210 0.340

133 0.065 0.080

134 0.099 0.230

135

136 0.026 0.052

137 0.105 0.230

138 0.120 0.250

139 0.017 0.014

140 0.080 0.240

141 0.099 0.280

142 0.024 0.018

143 0.018 0.002

144 0.020 0.003

145 2.170 20.000

146 0.062 0.017

147 0.120

148 0.084

149 0.021

150 0.097

151 0.057 0.026

152 0.290 0.380

153 0.036 0.032

154 0.094 0.380

155 0.590

156 1.495

157 0.210 0.056

158 0.028

159 0.021 0.016

160 0.017 0.007

161 0.026 0.034

162 0.019 0.006

163 0.037 0.027

164 0.019 0.002

165 0.038 0.018

166 0.040 0.016

167 0.061 0.025

168 0.011 0.002

169 0.035 0.010

170 0.040

171 0.021 0.005

172 0.011 0.001

173 0.035 0.018

174 0.037 0.011

175 0.020 0.006

176 0.024 0.016

177 0.011 0.001

178 0.027 0.006

179 0.025 0.013

180 0.034 0.007

181 0.068 0.021

182 0.038 0.079

183 0.029

184 0.009 0.002

185 0.033

186 0.066 0.025

187 0.063

188 0.052 0.007

189 0.020 0.045

190 0.008

191 0.065 0.150

192 0.024 0.010

193 0.065 0.370

194 0.025 0.004

195 0.013 0.004

196 0.015

197 0.870 0.730

198 0.054 0.018

199 0.110 0.024

200 0.027 0.019

201 0.130 0.054

202 0.020 0.012

203 0.035 0.021

204 0.010 0.005

205 0.016 0.009

206 0.024 0.026

207 0.035 0.012

208 0.036 0.025

209 0.024 0.005

210 0.020 0.017

211 0.011 0.006

212 0.018 0.013

213 0.065 0.051

214 0.014 0.006

215 0.048

216 0.079 0.026

217 0.052

218 0.015 0.003

219 0.059 0.040

220 0.050 0.079

221 0.043 0.120

222 0.053 0.033

223 0.023 0.015

224 0.031 0.038

225 0.059 0.066

226 0.088 0.070

227 0.012 0.013

228 0.027 0.022

229 0.042 0.012

230 0.017 0.007

231 0.019 0.002

232 0.020 0.013

233 0.011 0.002

234 0.053 1.600

235 0.039 1.100

236 0.019 0.019

237 0.016 0.014

238 0.010 0.001

239 0.440 0.430

240 0.053 0.032

241 0.009 0.000

242 0.060 0.069

243 0.170 0.450

244 0.150 0.120

245 0.109

246 0.340 0.740

247 0.110

248 0.075 0.077

249 0.043 0.026

250 0.051 0.075

251 0.178 0.340

252 0.095 0.230

253 0.080 0.220

255 0.063 0.083

256 0.210

257 0.440 0.660

258 0.058

259 0.140 0.082

260 0.067 0.250

261 0.190 0.170

262 0.140 0.190

263 0.094 0.067

264 0.056 0.088

265 0.110

266 0.200 0.260

267 0.100 0.150

268 0.059 0.029

269 50.000

270

271

272

273

274 0.051 0.016

275 0.057 0.038

276 50 20

277 50 20

278

279 0.11 0.039

280 0.089 0.15

281 0.072 0.021

282 0.091 0.15

283 0.064 0.082

284 0.044 0.01

285 0.048 0.027

286 0.061 0.027

287 0.029 0.003

288 0.026 0.01

289 0.018 0.01

290 0.021 0.029

291 0.02 0.003

292 0.044 0.033

293 0.064 0.12

294 0.049 0.041

295 0.031 0.037

296 0.024

297

298

299

300A 0.026 0.007

300B 0.024 0.003

301

302

303

304 0.021

305 0.078 0.077

306

307 0.056

308

309 0.037

310

311

312 0.037

313 0.1

314 0.46

315

316

317

318

320

321

322

323

324

325

326

327

328

329 0.089

330 0.1 0.028

331 0.11 0.021

332 0.01

333

334

335

336

337

338

339

340

341

342

343

344 0.024 0.013

345 0.035 0.006

346 0.018 0.0001

347 0.016 0.005

348 0.014 0.002

349 0.019

350 0.055

351

352 0.011

353 0.009

354 0.018

355 0.082

356 0.851

357 0.087

358 0.110

359 0.014

360 0.012

361 0.013

362 0.011

363 0.021

364 0.040

365 0.023

366 0.022

367 0.040

368 0.012

369 0.014

370 0.012

371 0.82

374 0.024

375

376 0.029

377 0.029

378 0.072

379 0.059

380 0.013

381 0.009

382 0.018

383 0.024

384 0.012

385 0.04

While preferred aspects of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch aspects are provided by way of example only. Numerous variations,changes, and substitutions will now occur to those skilled in the artwithout departing from the invention. It should be understood thatvarious alternatives to the aspects of the invention described hereincan be employed in practicing the invention. It is intended that thefollowing claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

What is claimed is:
 1. A compound having Structure III:

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; R²⁴ is H,—CN, —(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl), wherein: t is 0 or 1; u is 0 or 1; with theproviso that when u is 1, t is 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl; and R²⁵ is halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₂ alkyl orcyclopropyl.
 2. The compound of claim 1 wherein when L-Ar is

Ar is not


3. The compound of claim 1 wherein L-Ar is

and Ar is


4. The compound of claim 1 wherein L-Ar is

and Ar is


5. The compound of claim 4 wherein Ar is


6. The compound of any of claims 1-5 wherein R¹ is halogen, —CN or C1-C₂haloalkyl.
 7. The compound of claim 6 wherein R¹ L-Ar is —CN.
 8. Thecompound of any of claims 1-7 wherein R² is H.
 9. The compound of any ofclaims 1-8 wherein R²¹ is halogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl. 10.The compound of claim 9 wherein R²¹ is C₁-C₄ alkyl or C₃-C₅ cycloalkyl.11. The compound of claim 10 wherein R²¹ is C₁-C₂ alkyl, —CN or C₃-C₅cycloalkyl.
 12. The compound of claim 11 wherein R²¹ is C₁-C₂ alkyl. 13.The compound of claim 12 wherein R²¹ is —CH₃.
 14. The compound of any ofclaims 1-13 wherein R²² is H or C₁-C₂ alkyl.
 15. The compound of claim14 wherein R²² is H or —CH₃.
 16. The compound of claim 15 wherein R²² is—CH₃.
 17. The compound of any of claims 1-16 wherein R²⁴ is H, —CN,—(C₁-C₄ alkyl)-CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).
 18. The compound of claim 17 wherein R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₆ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).
 19. Thecompound of claim 18 wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).
 20. The compound of claim 19 wherein R²⁴ is—(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl).
 21. The compound of claim 20 wherein R²⁴is —CH₂—O—CH₃.
 22. The compound of claim 19 wherein R²⁴ is C₁-C₂ alkyl.23. The compound of claim 22 wherein R²⁴ is —CH₃.
 24. The compound ofclaim 18 wherein R²⁴ is C₃-C₆ cycloalkyl.
 25. The compound of claim 17wherein R²⁴ is —CN or —(C₁-C₂ alkyl)-CN.
 26. The compound of claim 25wherein R²⁴ is —CN.
 27. The compound of claim 25 wherein R²⁴ is —(C₁-C₂alkyl)-CN.
 28. The compound of claim 17 wherein R²⁴ is H, —CH₃, —CH₂OH,—CH₂OCH₃, —(CH₂)₂OH, —(CH₂)₂OCH₃ or —(CH₂)₂N(CH₃)₂.
 29. The compound ofclaim 17 wherein R²⁴ is methyl, isopropyl, cyclopropyl, —CN, or —(C₁-C₂alkyl)-CN.
 30. The compound of any of claims 1-20, 22, 24-25, 27 and 29wherein R²⁴ is substituted with one or more substituents selected fromC₁-C₂ alkyl, oxo, —CN, halogen, alkanoyl, alkoxycarbonyl, —OH and C₁-C₂alkoxy.
 31. The compound of claim 30 wherein R²⁴ is substituted with oneor more substituents selected from methyl, —F, methoxy, —C(═O)CH₃ and—C(═O)—OCH₃.
 32. The compound of claim 30 or 31 wherein R²⁴ issubstituted with two substituents that are the same or different. 33.The compound of claim 30 or 31 wherein R²⁴ is substituted with threesubstituents that are the same or different.
 34. The compound of any ofclaims 1-33 wherein R²⁵ is halogen, —CN, C₁-C₂ alkyl or cyclopropyl. 35.The compound of claim 34 wherein R²⁵ is halogen, C₁-C₂ alkyl orcyclopropyl.
 36. The compound of claim 34 wherein R²⁵ is —CN, —Cl or—CH₃.
 37. The compound of claim 36 wherein R²⁵ is —Cl.
 38. The compoundof claim 36 wherein R²⁵ is —CH₃.
 39. The compound of any of claims 1-35wherein R²⁵ is substituted with one or more substituents selected from—OH, halogen, C₁-C₂ alkyl and alkylcarbonyloxy.
 40. The compound ofclaim 39 wherein R²⁵ is substituted with one or more substituentsselected from —F, methyl and —O—C(═O)—CH₃.
 41. The compound of claim 39or 40 wherein R²⁵ is substituted with two substituents that are the sameor different.
 42. The compound of claim 39 or 40 wherein R²⁵ issubstituted with three substituents that are the same or different. 43.A compound of Structure IIIb:

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each R²⁴and R²⁵ is independently H, halogen, —CN, —(C₁-C₄ alkyl)-CN, C₁-C₄alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃—C cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; each u is independently 0 or 1; and eachR²⁴¹ is independently H or C₁-C₂ alkyl, wherein the compound is not:


44. The compound of claim 43 wherein when L-Ar is

Ar is not


45. The compound of claim 43 wherein L-Ar is

and Ar is


46. The compound of claim 45 wherein L-Ar is

and Ar is


47. The compound of claim 46 wherein Ar is


48. The compound of any of claims 43-47 wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.
 49. The compound of claim 48 wherein R¹ is —CN.
 50. Thecompound of any of claims 43-49 wherein R² is H.
 51. The compound of anyof claims 43-50 wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or4- to 6-membered heterocycle.
 52. The compound of claim 51 wherein R²¹is C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle. 53.The compound of claim 52 wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.54. The compound of claim 53 wherein R²¹ is C₁-C₂ alkyl.
 55. Thecompound of claim 54 wherein R²¹ is —CH₃.
 56. The compound of any ofclaims 43-55 wherein R²² is H or C₁-C₂ alkyl.
 57. The compound of claim56 wherein R²² is H or —CH₃.
 58. The compound of claim 57 wherein R²² is—CH₃.
 59. The compound of any of claims 43-58 wherein each R²⁴ and R²⁵is independently H, —CN, C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃—C cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).
 60. The compound of claim 59 wherein each R²⁴and R²⁵ is independently H, C₁-C₄ alkyl, —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).
 61. Thecompound of any of claims 43-58 wherein R²⁴ is H, C₁-C₄ alkyl, —(C₁-C₄alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄ alkyl)_(t)-O_(u)—(C₃-C₅cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to 6-membered heterocycle) or—(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).
 62. The compound of any of claims 43-58wherein R²⁴ is —CN, —Cl, C₁-C₄ alkyl or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl).63. The compound of claim 62 wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).
 64. The compound of claim 63 wherein R²⁴ is—(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl).
 65. The compound of claim 63 wherein R²⁴is C₁-C₄ alkyl.
 66. The compound of claim 65 wherein R²⁴ is —CH₃. 67.The compound of any of claims 43-58 wherein R²⁴ is hydrogen.
 68. Thecompound of any of claims 43-65 wherein R²⁴ is substituted with one ormore substituents selected from halogen, C₃-C₅ cycloalkyl and C₁-C₂alkoxy.
 69. The compound of claim 68 wherein R²⁴ is substituted with oneor more substituents selected from —F, cyclopropyl and —OCH₃.
 70. Thecompound of claim 68 or 69 wherein R²⁴ is substituted with twosubstituents that are the same or different.
 71. The compound of claim68 or 69 wherein R²⁴ is substituted with three substituents that are thesame or different.
 72. The compound of any of claims 43-58 or 61-71wherein R²⁵ is halogen, methyl, ethyl or cyclopropyl.
 73. The compoundof any of claims 43-58 or 61-71 wherein R²⁵ is —CN, —Cl, C₁-C₄ alkyl,—(C₁-C₄ alkyl)_(t)-O—(C₃-C₅ cycloalkyl) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄alkyl).
 74. The compound of claim 73 wherein R²⁵ is —CN, —Cl, —CH₃,—O—(C₃-C₅ cycloalkyl) or —O—(C₁-C₂ alkyl).
 75. The compound of claim 73wherein R²⁵ is —CN, —Cl or C₁-C₄ alkyl.
 76. The compound of claim 75wherein R²⁵ is —CH₃.
 77. The compound of claim 75 wherein R²⁵ is —Cl.78. The compound of any of claims 43-75 wherein R²⁵ is substituted withone or more halogen.
 79. The compound of claim 78 wherein R²⁵ issubstituted with one or more —F.
 80. The compound of claim 78 or 79wherein R²⁵ is substituted by two substituents.
 81. The compound ofclaim 78 or 79 wherein R²⁵ is substituted by three substituents.
 82. Acompound having Structure II:

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)_(t)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(t)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl), wherein:each t is independently 0 or 1; and each R²⁴¹ is independently H orC₁-C₂ alkyl.
 83. The compound of claim 82 wherein L-Ar is

and Ar is


84. The compound of claim 83 wherein L-Ar is

and Ar is


85. A compound of claim 84 wherein Ar is


86. The compound of any of claims 82-85 wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.
 87. The compound of claim 86 wherein R¹ is —CN.
 88. Thecompound of any of claims 82-87 wherein R² is H.
 89. The compound of anyof claims 82-88 wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or4- to 6-membered heterocycle.
 90. The compound of any of claims 82-88wherein R²¹ is H, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle.
 91. The compound of claim 89 or 90 wherein R²¹ is C₁-C₂alkyl or C₃-C₅ cycloalkyl.
 92. The compound of claim 91 wherein R²¹ isC₁-C₂ alkyl.
 93. The compound of claim 91 wherein R²¹ is C₃-C₅cycloalkyl.
 94. The compound of any of claims 82-93 wherein R²² is H orC₁-C₂ alkyl.
 95. The compound of claim 94 wherein R²² is H.
 96. Thecompound of claim 94 wherein R²² is C₁-C₂ alkyl.
 97. The compound ofclaim 96 wherein R²² is —CH₃.
 98. The compound of any of claims 82-97wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ alkyl). 99.The compound of claim 98 wherein R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂alkyl).
 100. A compound of Structure I:

or pharmaceutically acceptable salts thereof, wherein: L³ is —CH₂—,—CHR⁵⁰—, —O—, —NR⁵⁰—, —NC(O)R⁵⁰— or —NC(O)OR⁵⁰—, wherein R⁵⁰ is C₁-C₆alkyl, C₃-C₅ cycloalkyl, or 4- to 6-membered heterocycle; n is 1, 2, or3; m is 1 or 2 with the proviso that n+m≧3; L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen, or C₁-C₂ alkyl.
 101. Thecompound of claim 100 wherein L-Ar is

and Ar is


102. The compound of claim 101 wherein L-Ar is

and Ar is


103. The compound of any of claims 100-102 wherein R¹ is H, —CN, —C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl) wherein when R¹ is not H or —CN, R¹ is optionallysubstituted with one or more halogens.
 104. The compound of any ofclaims 100-102 wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.
 105. Thecompound of claim 104 wherein R¹ is —CN or C₁-C₂ haloalkyl.
 106. Thecompound of claim 105 wherein R¹ is —CN.
 107. The compound of claim 104wherein R¹ is —Cl.
 108. The compound of any of claims 100-107 wherein R²is H.
 109. The compound of any of claims 100-108 wherein R²¹ is halogen,C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-membered heterocycle.
 110. Thecompound of claim 109 wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.111. The compound of claim 110 wherein R²¹ is C₃-C₅ cycloalkyl.
 112. Thecompound of any of claims 100-111 wherein R²² is H or C₁-C₂ alkyl. 113.The compound of claim 112 wherein R²² is H.
 114. The compound of claim112 wherein R²² is C₁-C₂ alkyl.
 115. The compound of claim 114 whereinR²² is —CH₃.
 116. The compound of any of claims 100-115 wherein L³ is—N(CH₃)—.
 117. The compound of any of claims 100-116 wherein n is 2 andm is
 2. 118. The compound of any of claims 100-116 wherein n is 1 or 2.119. The compound of any of claims 100-116 wherein n is 1 and m is 2.120. A compound having Structure IIIc:

or pharmaceutically acceptable salts thereof, wherein: L-Ar

Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and each ofR²⁴ and R²⁵ is independently H, —C₁-C₄ alkyl, or halogen.
 121. Thecompound of claim 120 wherein L-Ar is

Ar is not


122. The compound of claim 120 wherein L-Ar is

and Ar is


123. The compound of claim 122 wherein L-Ar is

and Ar is


124. The compound of any of claims 120-123 wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.
 125. The compound of any of claims 120-124 wherein R²¹is halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle.
 126. The compound of claim 125 wherein R²¹ is —CH₃. 127.The compound of any of claims 120-126 wherein R²² is H.
 128. A compoundhaving Structure IV:

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle) or—O—(C₁-C₄ alkyl), wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to6-membered heterocycle; R²² is H, halogen or C₁-C₂ alkyl; and R²⁴ is H,C₁-C₄ alkyl, —(C₁-C₄ alkyl)-OH, —(C₁-C₄ alkyl)-N(R²⁴¹)₂, —(C₁-C₄alkyl)_(t)-O_(u)—(C₃-C₅ cycloalkyl), —(C₁-C₄ alkyl)_(t)-O_(u)-(4- to6-membered heterocycle) or —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), wherein: t is0 or 1; u is 0 or 1; with the proviso that when u is 1, t is 1; and R²⁴¹is H or C₁-C₂ alkyl.
 129. The compound of claim 128 wherein L-Ar is

and Ar is


130. The compound of claim 128 or 129 wherein R¹ is halogen, —CN orC₁-C₂ haloalkyl.
 131. The compound of claim 130 wherein R¹ is —CN. 132.The compound of any of claims 128-131 wherein R² is H.
 133. The compoundof any of claims 128-132 wherein R²¹ is halogen, C₁-C₄ alkyl, C₃-C₅cycloalkyl or 4- to 6-membered heterocycle.
 134. The compound of claim133 wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl.
 135. The compound ofclaim 134 wherein R²¹ is C₁-C₂ alkyl.
 136. The compound of claim 134wherein R²¹ is C₃-C₅ cycloalkyl.
 137. The compound of any of claims128-136 wherein R²² is H or C₁-C₂ alkyl.
 138. The compound of claim 137wherein R²² is H.
 139. The compound of claim 137 wherein R²² is C₁-C₂alkyl.
 140. The compound of claim 139 wherein R²² is —CH₃.
 141. Thecompound of any of claims 128-140 wherein R²⁴ is C₁-C₄ alkyl or —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl).
 142. The compound of claim 141 wherein R²⁴ is—(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl).
 143. A compound having Structure V:

or pharmaceutically acceptable salts thereof, wherein: L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L² is —NHR³⁵ or —C(O)NHR³⁵¹, wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; Het is a5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄ alkyl,—O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C₁-C₄alkyl) wherein when R¹ is not H, —CN or halogen, R¹ is optionallysubstituted with one or more halogens; each R² is independentlyhydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is H or —CH₃; R²¹ isH, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or 4- to 6-memberedheterocycle; R²² is H, halogen, or C₁-C₂ alkyl; and R³⁵ is —C(O)R³⁵¹,—C(O)NHR³⁵¹, C(O)OR³⁵¹ or S(O)₂R³⁵¹ wherein R³⁵¹ is C₁-C₆ alkyl, C₃-C₅cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl.
 144. Thecompound of claim 143 wherein when L-Ar is

Ar is not


145. The compound of claim 143 or 144 wherein L² is —NHR³⁵.
 146. Thecompound of claim 143 or 144 wherein L² is —C(O)NHR³⁵¹.
 147. A compoundhaving Structure VI:

or pharmaceutically acceptable salts thereof, wherein: each W, X, Y andZ is independently —N— or —CR²⁶— with the proviso that not more than 2of W, X, Y and Z are —N—; each R²⁶ is independently H, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —N(R²⁷)₂, —S(O)₂—(C₁-C₄ alkyl), or —C(O)—(C₁-C₄alkyl); each R²⁷ is independently H or C₁-C₄ alkyl or both R²⁷ are C₁-C₄alkyl and join to form a 3- to 6-membered ring together with the N towhich they are attached and wherein the ring optionally includes oneoxygen atom as one of the members of the ring; Ar is

Het is a 5- to 6-membered heteroaryl; R¹ is H, —CN, halogen, C₁-C₄alkyl, —O—(C₃-C₅ cycloalkyl), —O-(4- to 6-membered heterocycle),—O—(C₁-C₄ alkyl) wherein when R¹ is not H, —CN or halogen, R¹ isoptionally substituted with one or more halogens; each R² isindependently hydrogen, halogen or C₁-C₄ alkyl; R³ is H or F; R¹¹ is Hor —CH₃; R²¹ is H, halogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl or a 4- to6-membered heterocycle; and R²² is H, halogen or C₁-C₂ alkyl.
 148. Thecompound of claim 147 wherein Ar is


149. The compound of claim 147 or 148 wherein Y is —CR²⁶— wherein R²⁶ is—N(R²⁷)₂.
 150. The compound of any of claims 147-149 wherein X is —N—.151. A pharmaceutical composition comprising any of the compounds ofclaims 1-150 and a pharmaceutically acceptable carrier, excipient, ordiluent.
 152. A method of treating a viral infection in a subjectcomprising administering to the subject a therapeutically effectiveamount of any of the compounds of claims 1-150 or a pharmaceuticalcomposition of claim
 151. 153. The method of claim 152 wherein the viralinfection comprises hepatitis C infection.
 154. A method of treating acondition characterized by disregulation of a fatty acid synthasepathway in a subject by administering to the subject a therapeuticallyeffective amount of any of the compounds of claims 1-150 or apharmaceutical composition of claim
 151. 155. A method of treatingcancer in a subject comprising administering to the subject atherapeutically effective amount of any of the compounds of claims 1-150or a pharmaceutical composition of claim
 151. 156. The method of claim155 wherein the cancer is breast cancer, pancreatic cancer, or coloncancer.
 157. The method of claim 155, wherein the cancer is pancreaticcancer.